Neurocognitive Predictors of Behavioral Therapy Response in Depression

Anxiety and mood disorders are the most prevalent class of mental health disorders, with
lifetime prevalence estimated at 32% and 18%, respectively. These disorders have tremendous
personal and socioeconomic impacts (cost >$1500 per-patient/year) due to days lost at work,
increased health care utilization, and increased risk of mortality (e.g. cardiovascular
disease). First-line treatments for depression include pharmacologic (e.g. selective
serotonin reuptake inhibitors) and psychotherapeutic interventions (e.g. cognitive behavioral
therapy and behavioral therapy). While both are superior to placebo treatments, only 40-60%
of patients experience significant improvement and 15-25% of responders relapse within one
year. Thus, long-lasting improvements are experienced by less than 50% of patients. This
ineffectiveness has been moderately associated with symptom severity, illness duration, and
comorbidity, but these findings do not provide any strategies for improving treatment
effectiveness. The current study will seek to identify behavioral or cognitive-affective
predictors that indicate how well a patient is responding to treatment so that interventions
can be further individualized to more effectively treat refractory patients.

The aim of this study is to identify whether neural, biological, and behavioral responses
related to the arbitration of conflicting avoidance and approach drives can predict behavior
therapy response for depressed individuals. This aim will be accomplished using behavioral,
functional magnetic resonance imaging (fMRI), and genetic analyses pre and post Behavioral
Activation therapy. Research subjects will include treatment-seeking individuals with
clinically significant symptoms of unipolar depression. Diagnosis will be assessed using
structured clinical interviews. Anxious and depressive symptom severity, personality
characteristics, and general functioning will be collected via self-report paper-and-pencil
questionnaires. Objective measures of approach, avoidance, and conflict behavioral responses
will be collected using computer-administered testing and related neural responsivity will be
measured using fMRI. For exploratory aims, a blood draw will be collect pre and
post-treatment to examine genetic factors that may predict response to behavior therapy. This
research has the potential to identify neural and behavioral approach-avoidance
characteristics that can help predict which patients are likely to respond to behavior
therapy for depression (i.e., predictors of treatment effectiveness) and reveal targets for
future treatment modifications.

Aim 1: Clarify the potential contribution of approach-avoidance behaviors and neural
responses to depression symptom severity.

Hypothesis 1.1: Approach-related behaviors and conflict arbitration behavior will explain a
significant amount of variance in depressive symptoms, above and beyond avoidance-related
behavior.

Hypothesis 1.2: Activations within approach-related (i.e., striatum) and conflict arbitration
(i.e., lateral PFC) neural circuitry will explain significant variance in depressive symptom
severity above and beyond activations within avoidance-related (i.e., amygdala) neural
circuitry. Specifically, the investigators expect increased levels of depression to relate to
reduced striatal responsivity.

Aim 2: Identify approach-avoidance behaviors and neural responses that predict the
effectiveness of behavioral activation therapy (BA) for depressed subjects.

Hypothesis 2.1: Approach-related behaviors and/or conflict arbitration behavior will help
predict treatment response above and beyond avoidance-related behavior and baseline symptom
severity. Specifically, the investigators expect that decreased reward sensitivity will
predict nonresponse of depressed patients to BA.

Hypothesis 2.2: Approach-related and conflict arbitration neural circuitry will help to
predict treatment response above and beyond activations within avoidance-related neural
circuitry. Specifically, the investigators expect striatal responsivity to reward to predict
response of depressed patients to BA.

Aim 3: Identify whether functional improvement with BA is associated with change in
approach-avoidance behaviors and/or neural responses.

Hypothesis 3.1: The level of change in reward sensitivity will positively relate to the level
of improvement in overall functioning with BA.

Inclusion Criteria:

1. Age: 18-55

2. All genders

3. All races

4. Eligibility as clinically significant depression will be determined by:

- Scoring greater than 9 on the Patient Health Questionnaire (PHQ-9) or meeting
diagnostic criteria for Diagnostic and Statistical Manual (DSM-5) Major
Depressive Disorder

- Self-report that they are interested in obtaining treatment for depression.

- Through structured diagnostic interviews, it is determined that depressive
symptoms are the primary disorder of concern.

5. Able to provide written, informed consent

6. Have sufficient proficiency in English language to understand and complete interviews,
questionnaires, and all other study procedures

Exclusion Criteria:

1. Has a history of unstable liver or renal insufficiency; glaucoma; significant and
unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic,
hematologic, rheumatologic, or metabolic disturbance; or any other condition that, in
the opinion of the investigator, would make participation not be in the best interest
(e.g., compromise the well-being) of the subject or that could prevent, limit, or
confound the protocol-specified assessments.

2. A history of drug abuse in the past 6 months, including alcohol, cocaine, marijuana,
opiates, amphetamines, methamphetamines, phencyclidine, benzodiazepines, barbiturates,
methadone, and oxycodone. Current alcohol use will be ruled out using a breath test
and urine testing will be used to rule out current use of other drugs of abuse.

3. Has any of the following Diagnostic and Statistical Manual (DSM-5) disorders:

- Schizophrenia Spectrum and Other Psychotic Disorders

- Bipolar and Related Disorders

- Obsessive-Compulsive and Related Disorders

- Anorexia or Bulimia Nervosa

- Substance use disorder within 6 months

4. Moderate to severe traumatic brain injury (>30 min. loss of consciousness or >24 hours
posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological
deficits, neurological disorders, or severe or unstable medical conditions that might
be compromised by participation in the study.

5. Active suicidal ideation with intent or plan

6. Current use of a medication that could affect brain functioning (e.g., anxiolytics,
antipsychotics, or mood stabilizers). However, participants reporting current use of
prescribed antidepressants (selective serotonin reuptake inhibitors) will be included
as long as the dose has been stable for 6 weeks prior to enrolling in the study.

7. Prescription of a medication outside of the accepted range, as determined by the best
clinical practices and current research

8. Taking drugs that affect the fMRI hemodynamic response (e.g., methylphenidate,
acetazolamide, excessive caffeine intake > 1000 mg/day).

9. MRI contraindications including: cardiac pacemaker, metal fragments in eyes/skin/body
(shrapnel), aortic/aneurysm clips, prosthesis, by-pass surgery/coronary artery clips,
hearing aid, heart valve replacement, shunt (ventricular or spinal), electrodes, metal
plates/pins/screws/wires, or neuro/bio-stimulators (TENS unit), persons who have ever
been a professional metal worker/welder, history of eye surgery/eyes washed out
because of metal, vision problems uncorrectable with lenses, inability to lie still on
one's back for 60-120 minutes; prior neurosurgery; tattoos or cosmetic makeup with
metal dyes, unwillingness to remove body piercings, and pregnancy

10. Unwillingness or inability to complete any of the major aspects of the study protocol,
including magnetic resonance imaging (i.e., due to claustrophobia), blood draws, or
behavioral assessment. However, failing to complete some individual aspects of these
assessment sessions will be acceptable (i.e., being unwilling to answer individual
items on some questionnaires or being unwilling to complete a behavioral task).

11. Non-correctable vision or hearing problems