Genomics Used to Improve DEpression Decisions

Major depressive disorder (MDD) is a highly prevalent (Hasin et al., 2005) mental disorder
and a leading source of disease burden worldwide (Lopez et al., 2006). Epidemiological
studies estimate 12-month and lifetime prevalence for MDD in the United States to be 5.3% and
13.2%, respectively (reviewed in Blanco et al., 2010). MDD is expected to be the second
greatest cause of disability by 2020 and has been shown to cause significant morbidity,
affecting people's ability to work, function in relationships, and engage in social
activities. Moreover, MDD increases the risk of suicidal ideation, attempted suicide, and
death by completed suicide.

Prospective longitudinal studies of patient samples show that MDD is a chronic illness,
characterized by remitting and recurrent depressive episodes (Solomon et al., 1997; Mueller
et al., 1999). A major depressive episode is characterized by a low mood or an inability to
experience pleasure (anhedonia), or both, for more than 2 weeks, combined with several
cognitive and vegetative symptoms and the occurrence of distress or impairment (reviewed in
Rot et al., 2009). In the US, nearly 1 in 5 people will experience a major depressive episode
at some point in their lives (reviewed in Rot et al., 2009). Drugs currently available to
treat depression fall into the categories of those that have their main effect by increasing
norepinephrine (NE) (the tricyclic or tetracyclic antidepressants [TCAs]), those that
increase serotonin (5-HT) (the selective serotonin reuptake inhibitors [SSRIs]), and those
that increase both NE and 5-HT (the monoamine oxidase inhibitors [MAOIs] and the serotonin
and norepinephrine reuptake inhibitors [SNRIs]). While all antidepressants achieve similar
levels of efficacy, treatment failures are relatively high ranging from 30 to 60% (Simpson
and DePaulo). Additionally, many of these compounds are associated with significant adverse
events (AEs).

The GeneSight Psychotropic product is a pharmacogenomic decision support tool that helps
clinicians to make informed, evidence-based decisions about proper drug selection, based on
the testing for clinically important genetic variants in multiple pharmacokinetic and
pharmacodynamic genes that affect a patient's ability to tolerate or respond to medications.

The GeneSight Psychotropic product contains the most commonly prescribed antidepressant and
antipsychotic medications, including a full representation of the SSRI and SNRI drug classes.

Tricyclic antidepressants, an MAOI, and typical and atypical antipsychotics are also
represented.

The clinical utility of GeneSight Psychotropic has been evaluated in three previous
prospective trials. Hall-Flavin et al reported the results of an open-label pilot study (n =
44) comparing GeneSight guided treatment to treatment as usual (TAU) without the benefit of
pharmacogenomic testing (2012). The GeneSight guided arm demonstrated a 30.8% improvement in
HAM-D17 score by the end of the 8 week treatment period, compared to an 18.2% improvement in
the TAU arm (p = 0.04). Results of the larger (n = 165) open-label trial (Hall-Flavin, et al
2013) mirrored these findings, demonstrating a 46.9% improvement in HAMD17 score in the
GeneSight arm, compared to a 29.9% improvement in the TAU arm (p < 0.0001). The third trial
used a randomized, double-blind trial design (n = 51). Due to the small sample size, the
trial was underpowered to detect a significant difference in improvement between the two arms
(TAU and GeneSight). However, effect sizes of improvement reflected those seen in previous
trials. The GeneSight group experienced a 30.8% improvement in HAMD17, compared to 20.7% in
TAU. Odds ratios for response were calculated, showing that GeneSight-guided subjects had a
2.14 times greater likelihood of response compared to TAU subjects, which was similar to the
4.67 (smaller trial) and 2.06 (larger trial) odds ratios calculated for the other two
studies.

Previous studies utilizing an open-label design have shown significant improvement in patient
outcomes following use of the GeneSight test. However, although effect sizes were similar to
those seen in the open-label studies, a small (n = 51) blinded, randomized controlled trial
did not detect a statistically significant outcome. Therefore, the primary rationale for this
trial is to replicate previous findings of improvement in clinical outcomes in subjects
treated with the benefit of GeneSight testing utilizing a double-blind, randomized control
trial (RCT) design.

It is expected that results from this trial will be used to inform guidelines for the use of
pharmacogenomic testing for the treatment of major depressive disorder. Results may also be
shared with regulatory bodies in the United States and abroad.

Inclusion Criteria:

- Be able to understand the requirements of the study and provide written informed
consent to participate in this study; a signed and dated ICF will be obtained from
each patient before participation in the study;

- Have provided written authorization for the use and disclosure of their protected
health information;

- Be ≥18 years of age;

- Suffer from a Major Depressive Episode meeting DSM-IV-TR criteria;

- Have had an inadequate response within the current episode to at least 1 psychotropic
treatment. Inadequate response is defined as inadequate efficacy after 6 weeks of a
psychotropic treatment or discontinuation of a psychotropic treatment due to AEs or
intolerability;

- Have a total baseline score on the QIDS-C16 and QIDS-SR16 rating scale ≥11;

- Agree to abide by the study protocol and its restrictions and be able to complete all
aspects of the study, including all visits and tests.

Exclusion Criteria:

- Patients posing a serious suicidal risk and/or in need of immediate hospitalization as
judged by the investigator;

- Patients with a diagnosis of Bipolar I or II disorder;

- Patients with a current Axis I diagnosis of:

1. Delirium

2. Dementia

3. Amnestic and other cognitive disorder

4. Schizophrenia or other psychotic disorder;

- Patients having experienced hallucinations, delusions, or any psychotic symptomatology
within the current depressive episode or during prior depressive episodes;

- Patient is currently in an inpatient facility;

- Patients with a history of hypothyroidism unless taking a stable dose of thyroid
medication and asymptomatic or euthyroid for 6 months;

- Patients who meet DSM-IV-TR criteria for any significant current substance use
disorder;

- Patients with significant unstable medical condition; life threatening disease;
hepatic insufficiency (3X ULN for AST and/or ALT); liver transplant recipient;
cirrhosis of the liver; need for therapies that may obscure the results of treatment
and/or of the study; malignancy (except basal cell carcinoma) and/or chemotherapy
within 1 year prior to screening; malignancy more than 1 year prior to screening must
have been local and without metastasis and/or recurrence, and if treated with
chemotherapy, without nervous system complications;

- Participation in another clinical trial within 30 days of the screening visit;

- Anticipated inability to attend scheduled study visits;

- Patients who in the judgment of the Investigator may be unreliable or uncooperative
with the evaluation procedure outlined in this protocol;

- Patients with a history of prior pharmacogenomic testing;

- Any change in psychotropic medication (including change in dosage) between screening
and randomization;

- Patients receiving ECT, DBS or TMS treatment (should a Subject receive any of these
treatments they must be discontinued from the study);

- Patients who are known to be pregnant or lactating;

- Patients with a history of gastric bypass surgery.