Antidepressant Treatment at an Inner City Asthma Clinic

A 12-week, randomized, double-blind, parallel-group, placebo-controlled acute phase trial of
escitalopram is proposed in 222 persons with asthma and Major Depressive Disorder (MDD). This
sample will consist of 80 stratified into the High severity group which will consist of a
baseline score > or = 20 on the 17-item Hamilton Rating Scale for Depression (HRSD) and > or
= 3 courses of oral corticosteroids in the past 12 months. A separate group stratified into
the Low severity group of 142 with MDD and asthma but HRSD-17 scores of < 20 and < 3 courses
of oral corticosteroids in the past 12 months. A 16 week continuation phase is also proposed
for depression responders at week 12. The participants will be recruited at the Parkland
Hospital Health System (PHHS) Asthma and Allergy Clinics and Aston Clinic using the
Self-Report Screening Tool for Depression (2-SRSD), a brief depression questionnaire, as part
of routine clinical practice. Potential participants will be given an appointment scheduled
at the PI's office to complete baseline assessment at which time written informed consent
will be obtained before any study-specific assessments are completed. At the baseline
appointment, the RA will administer the Structured Clinical Interview for DSM-IV (SCID) at
baseline to establish a current diagnosis of MDD. Participants meeting all inclusion criteria
will then be administered the IDS-SR30, the SF-36, the Asthma Control Questionnaire (ACQ),
Mini Asthma Quality of Life Questionnaire (Mini AQLQ), the Cumulative Illness Rating Scale
(CIRS), the PRD-III Somatic Symptom Scale (PRD-III) for side effects, a blood draw for
routine laboratory analyses, and forced expiratory volume in 1-second percentage of normal
(FEV1%) will be assessed using a portable spirometer. Self-reported asthma-related emergency
room visits and hospitalizations will be quantified for the past 12 months.

Participants will receive a clinical psychiatric evaluation by one of the investigators to
confirm the diagnosis and that the participant meets entry criteria. Steroid inhaler dose
monitoring using the counter already included by the manufacturer will begin at this time.
After the participant is determined to qualify, the steroid inhaler counter will be used to
assess baseline adherence. Participants will be randomized and receive either escitalopram or
a placebo identical in appearance. Each participant will then be given a 14-day supply of
active medication (escitalopram 10 mg) or placebo and asked to return for a follow-up
appointment in two weeks. Each participant will be given a phone number to reach the
Principle Investigator (PI) and Research Assistant (RA) 24 hours a day. The RA will obtain
written consent to inform the physician treating their asthma of their participation in the
study. Each participant will then return for follow-up appointments twice per month at which
time they will repeat the outcome measures according to the schedule given below. Pill counts
will be conducted, MEMS caps analyzed and a list of current medications and doses will be
obtained at each visit. Participants will be evaluated by both the RA and PI at each
follow-up appointment. Participants who have not shown evidence of adequate response (< 30%
decrease in HRSD) to the antidepressant at week 4, and who do not have side effects, will
have the dose increased to two tablets (20 mg of active medication or placebo). At week 12,
responders (HRSD reduction ≥50% from baseline) will continue on blinded treatment with
assessments every 4 weeks for an additional 16 weeks (continuation phase). Nonresponders will
be removed from the study and given standard treatment by an unblinded psychiatrist (Dr.
Nakamura) until referral can be made for further treatment. Continuation phase will begin at
the final week 12 assessment for responders. They will be given a 4-week supply of medication
at the dose they are taking at week 12, and instructions to call if they experience a
worsening in symptoms (e.g., decrease in sleep, suicidal thoughts) between the 4-week
appointments, and an appointment with a study physician will be arranged. The HRSD will be
assessed at any interim appointments and the participant discontinued if they meet
discontinuation criteria. Treatment referral will be arranged as in the acute phase study. At
completion of 28 weeks, they will be referred for further treatment as appropriate, with
their PCP, the Parkland Psychiatry Clinic, a private psychiatrist, a UT Southwestern Medical
Center, or the county Mental Health Mental Retardation (MHMR) system. Parking/bus tokens will
be provided. A final visit for safety, to assess follow-up adherence and collect asthma and
depression outcome data will be arranged 4 weeks after the last appointment (e.g.,
discontinuation at end of acute phase, end of continuation phase, or if discontinued early
for any reason).

The assessment schedule is designed to approximate good clinical practice for depression and,
thus, may be somewhat less intensive than in some antidepressant trials. The following
assessment instruments will be used in this investigation. A two-item, self-report screening
tool for depression (2-SRSD) taken from the Primary Care Evaluation of Mental Disorders
Procedure (PRIME-MD) screening interview will be used to detect suspected cases of depression
among asthma clinic patients. The specificity of the 2-SRSD in this population was 57%. Thus,
we expect to identify almost all true positives, with a substantial number of false
positives. A positive answer to either 1) "During the past month, have you often been
bothered by feeling down, depressed, or hopeless?" or 2) "During the past month, have you
often been bothered by little interest or pleasure in doing things?" will be considered a
possible case of depression and qualify for further assessment. MDD is defined as at least
five of nine symptoms that must include depressed mood or loss of interest and can also
include psychomotor changes, appetite changes or weight loss, sleep changes, decreased
concentration, guilt, decreased energy levels (lassitude), and suicidal ideation. The
symptoms must occur at the same time and last for at least 2 weeks and be associated with a
change in functioning. The symptoms must not be the direct physiologic effect of a drug or
medical illness (e.g., hypothyroidism) or bereavement. MDD is diagnosed using a structured
clinical interview that addresses each symptom and uses information from the patient, family,
physicians, and medical records to establish the diagnosis.

The clinician version of the structured Clinical Interview for DSM-IV (SCID) is a brief
structured interview for major Axis I disorders in DSM-IV including major depressive
disorder, dysthymic disorder, bipolar disorders, psychotic disorders, anxiety disorders,
eating disorders, and alcohol and substance abuse/dependence. The Hamilton Rating Scale for
Depression (HRSD, 17-item version) is an observer-rated measure of depressive symptomatology.
The HRSD will be administered at every visit. The Inventory of Depressive
Symptomatology-Self-report (IDS-SR30) is a 30-item self-report scale that assesses depressive
symptom severity. The IDS-SR30 will be administered at every visit. The Hamilton Rating Scale
for Anxiety (HRSA) is a 14-item observer rating scale that assesses the degree and pathology
associated with anxiety such as anxious mood, tension, fear, and insomnia. The HRSA will be
administered at every visit. Asthma symptoms will be assessed at every visit using the Asthma
Control Questionnaire (ACQ). Pulmonary function will also be assessed at every visit by
spirometry, using equipment meeting the standards of the ATS, and calibrated according to the
manufacturer's recommendations. Spirometry will be performed according to ATS guidelines, as
the best of three acceptable efforts. Spirometry will be measured before, and 10 minutes
after, two puffs of albuterol are administered via metered dose inhaler. Bronchodilator
response is calculated as [(post FEV1 - pre FEV1)/pre FEV1], and converted to a percent
improvement.

The Psychobiology of Recovery in Depression-III Somatic Symptom Scale (PRD-III) is a 24 item,
side effects scale developed for a longitudinal depression study. The PRD-III covers a wide
range of common medication side effects and can be quickly and easily administered by a
clinician. The PRD-III will be administered at every visit. Asthma-related quality of life
will be assessed with the Mini-AQLQ, a 15 item, self-administered scale measuring functional
impairments troublesome to adult asthma patients. Mini-AQLQ showed good responsiveness,
reliability, and construct validity compared to the longer 32 item version. Both versions of
the Mini-AQLQ correlate well with SF 36 mental and physical subscales and ACQ scores (asthma
symptoms), but not with spirometry or beta-agonist use. The Mini-AQLQ will be administered at
baseline, week 4, week 8, week 12, and at exit or if continued, week 28. General functioning
will be assessed with the 36-Item Short Form Health Survey (SF-36), a self-reported tool used
to assess physical and mental functioning. The scale consists of summary measures of physical
and mental health that can be further divided into scales for physical functioning,
role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and
mental health. Scores above the normative score of 50±10 indicate better than average
functioning while scores below 50 suggest below normal functioning. The SF-36 will be
administered at baseline, week 4, week 8, week 12, and at exit or if continued, week 28.

Medical illness burden will be assessed at baseline and at exit with the Cumulative Illness
Rating Scale (CIRS), a valid and widely used 13-item, 0-4, clinician-rated scale that
assesses medical impairment related to major organ systems. Medical history and review of
systems is used for the rating. The scale will be rated by a study physician. The scale has
been used in other recent antidepressant trials to assess medical illness burden. The
Perceived Stress Scale (PSS-10) is a 10-item, 0-4 self-report scale that assesses stressful
feelings and thoughts in the past month. The PSS-10 has adequate reliability and validity and
is a better predictor of some outcomes (e.g. depressive and physical symptoms, utilization of
health services, social anxiety) than were life-event scores. The PSS-10 appears to provide a
general appraisal of life stress. The PSS-10 will be administered at baseline, week 4, week
8, week 12, and at exit or if continued, week 28.

Specific Primary and Secondary Outcome Measures associated with primary and secondary aims
include:

Primary Aim:

1. Escitalopram treatment will be associated with greater improvement in asthma symptoms,
using ACQ measure, than placebo in outpatients with asthma and MDD.

Secondary Aim:

1. Escitalopram treatment will be associated with greater depressive symptom remission rates,
using HRSD, than placebo in outpatients with asthma and MDD.

Inclusion Criteria:

- Acute phase:

- Physician diagnosis of asthma and currently receiving asthma treatment, Current
diagnosis of MDD confirmed by the SCID and clinical assessment by a psychiatrist

- Baseline HRSD ≥ 15

- Baseline ACQ score of ≥ 1

- Ages 18-70 years to include the range of ages typically treated at our referral
sources

- No changes in asthma medications, oral corticosteroid use, or treatment for
respiratory tract infections in the past 2 weeks

- Both male and female

- English- or Spanish-speaking

- Continuation phase:

- Completed week 12 assessment of acute treatment phase

- Acute phase responders (defined as a baseline to week 12 reduction in the HRSD
score of 50% or greater)

Exclusion Criteria:

- Acute phase:

- Current substance and alcohol abuse/dependence

- Current daily tobacco use

- Severe or life threatening medical illness that would make completion of study
unlikely (e.g. myocardial infarction)

- MDD with psychotic features (delusions, hallucinations, disorganized thought
processes, etc), bipolar disorder, schizophrenia, schizoaffective disorder, or
substance-induced mood disorder and mood disorders secondary to a general medical
condition

- Vulnerable populations including mentally retarded persons or those with other
severe cognitive impairment, prison or jail inmates, pregnant or nursing women or
women of childbearing age who will not use UTSW IRB-approved methods of birth
control or abstinence during the study

- Initiation on other psychotropic medications within the past 2 weeks

- High risk for suicide defined as > 1 past attempts or current suicidal ideation
with plan and intent or HRSD suicide question score of ≥ 2

- Use of antidepressants at therapeutic doses for depression within 1 week of study
entry. Potential participants taking antidepressants (other than escitalopram)
for depression may be enrolled following 1 week washout if they currently meet
depression entry criteria and have been taking the medication for at least 4
weeks at a therapeutic dose (non-responder)

- Patients currently taking but not responding to escitalopram (current study
drug). At week 8, if HRSD is < 25% decrease from HRSD baseline score, clinician
may consider discontinuation since response by week 12 in these patients is
unlikely

- Continuation phase:

- Development of exclusion criteria for acute phase (i.e., current suicidal
ideation with plan and intent)

- HRSD score > 50% of baseline score (no longer meets criteria as a responder)