Effects of Treatment on Decision-making in Major Depression

During episodes of depression patients with major depressive disorder (MDD) may make
sub-optimal decisions based on exaggerated negative beliefs about themselves, the future, or
the world around them. These disruptions in decision-making contribute adversely to quality
of life, in both work and personal realms. Although effective treatments for depression are
available, very little work has explored the effects of treatment on how people make
decisions. The specific aspects of decision-making that differ between depressed and health
control individuals are unknown, and whether any changes in these decision-making features
occur as a result of improvement from depression, or whether medication treatment itself can
lead to changes in decision-making, even in the absence of clinical improvement.

In this trial, fifty participants with current major depressive disorder who are not
receiving an antidepressant medication and fifty healthy controls will complete
questionnaires and computerized tasks to assess their decision-making styles. There will be
three visits for depressed patients and two for healthy controls (the first and third
visits). The first visit will involve interviews and questionnaires to assess the
participant's level of depression, medical history and quality of life. Participants will
then complete the decision-making tasks, and will earn between $5-40 based on their choices,
in order to make the decisions on the computer tasks financially meaningful. At the
completion of this visit, depressed patients will be prescribed an FDA-approved
antidepressant, chosen in consultation with the treating psychiatrist. Patients will be
responsible for paying for the prescription themselves. After two weeks on the medication,
the patient will be seen for a follow-up visit to ensure tolerability of the medicine. After
six weeks on the medicine, patients and healthy controls will return to repeat the
questionnaires and the computer based decision-making tasks, and will again earn between
$5-40 based on their performance.

The overall goal of this study will be to identify whether decision-making characteristics in
people with major depression is affected by treatment, and whether depressed patients make
decisions differently from healthy controls. A total of 4 decision-making tasks and one
control task will be administered via computer to eligible subjects. The specific tasks are:

1. Risk Task - This task assesses tolerance of risk by having participants decide whether
they wish to accept a specific dollar payout, or to play a lottery with an uncertain
payout.

2. Balloon Analogue Risk Task - The participant is presented with a balloon and offered the
chance to earn money by pumping the balloon up by clicking a button. Each click causes
the balloon to incrementally inflate and money to be added to a counter up until some
threshold, at which point the balloon is over inflated and explodes. Thus, each pump
confers greater risk but also greater potential reward. If the participant chooses to
cash-out prior to the balloon exploding then they collect the money earned for that
trial, but if balloon explodes earnings for that trial are lost. Participants are not
informed about the balloons breakpoints; the absence of this information allows for
testing both participants' initial responses to the task and changes in responding as
they gain experience with the task contingencies.

3. Temporal Discounting Task - Participants are initially asked to choose between taking an
immediate reward now or a larger reward at some time in the future. Decisions for seven
time points over a 10-year time frame are proposed. The task is then repeated using
choices between immediate and delayed losses, based on the same seven time points. This
task assesses the manner in which subjects value immediate outcomes compared to
long-term consequences.

4. Ultimatum Game - The ultimatum game (UG) is a well-established game-theoretical paradigm
commonly employed in behavioral economics to measure emotional reactions to unfair
offers. In the UG, two subjects sequentially exchange real monetary amounts.
Specifically, a proposer is provided with a sum of money by the experimenter ($10), and
asked to share this amount of money with another player, the responder. The responder
then decides whether to accept or reject the offer made by the proposer. If the
responder accepts the offer, both players receive the respective amounts from the
proposer's offer. If she rejects the offer made by the proposer, both players receive
nothing ($0). This is best illustrated via the following two potential scenarios: 1. the
proposer offers a fair split of $5 for himself and $5 for the responder. This is an
offer that is typically accepted by a great majority of responders. 2. The proposer
offers a split of $9 for himself and $1 for the responder. Such offers are commonly
rejected by the majority of responders, despite incurring a financial loss of $1.

5. Continuous Performance Task - This task involves identifying patterns of numbers briefly
displayed on a computer screen. This task will serve as a control variable for attention
in analyzing the results of the decision-making tasks.

Inclusion Criteria for MDD Subjects:

1. Male or female, age 18-65

2. Primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision (DSM-IV TR) Diagnosis of Major Depressive Disorder.

3. Has a 17-item Hamilton depression rating scale (HDRS-17) score >=16.

4. Ability to visually read and understand English language

5. Not currently taking an antidepressant.

6. Women of reproductive potential must be willing to take a medically approved form of
birth control throughout the duration of the study.

Inclusion Criteria for Healthy Control Subjects:

1. Male or female, age 18-65

2. No current DSM-IV TR diagnosis of a mental illness.

3. No lifetime history of Major Depressive Disorder or Dysthymia.

4. Has a 17-item Hamilton depression rating scale (HDRS-17) score ≤7.

5. Ability to visually read and understand English language

6. Not currently taking any psychoactive medication

Exclusion Criteria for all subjects:

1. Has met criteria at any time during their life for bipolar disorder, a primary
psychotic disorder (e.g. schizophrenia), or dementia.

2. Meet criteria for substance abuse or dependence within three months of the screening
visit.

3. Presents with a clinically significant suicide risk, as assessed by a study physician.

4. Presence of any unstable or central nervous system-related medical illness that would
interfere with cognition or participation.

5. Women who are currently pregnant or lactating, or plan to become pregnant during the
study.