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Understanding anti-depressant treatment failure in an underserved vulnerable population

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Understanding anti-depressant treatment failure in an underserved vulnerable population

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Understanding Anti-Depressant Treatment Failure in an Underserved Vulnerable
Population

by
Robert Earle Featherstone

A Thesis presented to the
FACULTY OF THE KECK SCHOOL OF MEDICINE of USC
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL, BIOMEDICAL AND TRANSLATIONAL INVESTIGATIONS)

August 2022

Copyright 2022 Robert Earle Featherstone
ii
TABLE of CONTENTS

List of Tables iv

List of Figures v

Abstract vi

Introduction 1

Chapter 1: Depression in Latino/as 1
Introduction 1
Prevalence 1
Characteristics of Depression in Latino/as 3
Treatment Resistant Depression 3
Treatment Resistance in Latino/as 4
Current Evidence for Treatment Resistance in Latino/as 5

Chapter 2: Factors that predict Treatment Resistance 8
Social – Environmental. 8
Early Life Stress/Adverse Childhood 8
Discrimination 10
Acculturative Stress 11
Other 11
Psychiatric Co-morbidities 12
Anxiety 12
Bipolar Features 12
Psychotic Features 13
Biological 13
Developing and Model of TRD in Latino/as 14

Chapter 3: Methods 16
Design 16
Interview 16
Maudsley Staging Method 19
Statistical Analyses 20

Chapter 4: Results 21
Demographic Information 21
Clinical Characteristics 22
Primary Analysis 23
Secondary Analyses 23
Suicide 23
Perceived Stress 23
Country of Birth 24
iii
Social Network and Health 25

Chapter 5: Discussion 27
Conclusions 32

Bibliography 33

iv
LIST of TABLES

Table 1 21

Table 2 22

Table 3 24

v
LIST of FIGURES

Figure 1 24

vi
ABSTRACT
Depression has been identified as the leading global cause of health-related disability
by the World Health Organization. Approximately 50% of depressed patients fail to
show significant improvement following treatment with conventional anti-depressant
medications (ADM), a phenomenon that has been termed treatment-resistant (TR)
depression. TR contributes greatly to the economic and personal burden of depression.
As such, researchers have been increasingly focused on identifying factors that lead to
and predict treatment resistance. Most of this research has been conducted in non-
Latino/a/a Caucasian populations. Consequently, little is known about TR in ethnic
minority patients, either in terms of prevalence or etiology. The current study marks an
initial attempt to begin to address this gap. Based on review of current research
Adverse Childhood Events (ACEs) was selected as the most likely factor to be linked to
treatment-failure in this population. ACEs were determined using the Adverse Childhood
Event checklist. Treatment success/failure was determined using the Maudsley Staging
method. Fifty-one Latino/a participants were assessed, of which 80.4% were female,
with a mean age of 42.5 years (SD 13.3), and primarily of Mexican descent (82.7%).
Logistic regression was used to assess the relationship between number of ACEs and
treatment success (yes/no). No association was found between ACE exposure and
treatment resistance. Secondary analyses found a strong relationship between adult
stress experience and treatment-response, as well as ACE exposure and previous
suicide attempt. It is possible that ACE measures developed in other populations fail to
accurately characterize Latino/a experiences, or that adult stress exposure plays a more
fundamental role
1
Chapter 1: Depression in Latino/as

Introduction
Depression is a catastrophic mental illness that causes immense interpersonal, social
and economic distress. The lifetime prevalence of depression in the United States is
around 15% (Bromet et al., 2011). Approximately 1/3 of individuals with depression
experience a chronic, life-long, unremitting illness, while other subjects show a chronic
alternating pattern of remission and relapse (Torpey and Klein, 2008). Depression is
associated with high rates of social, occupational and cognitive disability and greatly
reduced quality of life (Kessler, 2012). There is high comorbidity between depression
and several non-psychiatric illnesses, such as chronic pain, diabetes, cardiovascular
disease, high blood-pressure and chronic respiratory disorders (Kessler, 2012), leading
to increased hospitalization and significantly reduced life-span (Cuijpers and Schoevers,
2004). Likewise, depression greatly elevates risk of suicide, being present in up to 2/3 of
all suicides (Hawton et al., 2013). The indirect costs stemming from increased morbidity,
decreased productivity, and direct costs associated with medical treatment for
depression produces an estimated economic burden of approximately $200 billion
dollars in the United States, and this is expected to rise dramatically in the near future
(Greenberg et al., 2015).

Prevalence
Overall, Latino/a Americans show similar prevalence for depression to non-Latino/a
Whites(Alegria et al., 2008a; Gonzalez et al., 2010; Lewis-Fernandez et al., 2005;
2
Menselson et al., 2008; Perreira et al., 2015). Significant differences in depression
prevalence have been shown across Latino/a subgroups, with Mexican Americans
showing lower and Puerto-Rican-Americans higher rates of depression compared to
each other and to non-Hispanic Whites (Oquendo et al., 2001). Likewise, country of
birth appears to affect depression prevalence, as lower rates have been reported in
non-US born Americans compared to US-born Americans and non-Latino/a Whites.
This may be part of a larger trend for improved health outcomes in non-US born
Latino/as that has been termed the “immigrant” or “Hispanic” paradox. The Hispanic
paradox has most reliably been reported in Mexican-American Latino/as relative to
other Latino/a groups, at least in terms of depression prevalence (Alegria et al., 2008a;
Perreira et al., 2015; Vega et al., 2004). This phenomenon is unlikely to be due to
selection differences, such as the healthy migrant effect, since likelihood of developing
depression in non-US born Latino/as increases as a function of length of residence in
the US (Perreira et al., 2015; Vega et al., 2004). Increased rates of depression in US-
born or long-term US-resident Latino/as are likely related to some aspect of life in the
US, possibly discrimination (Perreira et al., 2015). Most studies have assessed
depression rates either as 12-month or lifetime prevalence which fails to capture
differences in depression chronicity or duration of depressive episode. Studies that have
included assessment of these measures have tended to find higher levels in Latino/as
compared to non-Latino/a Whites (Breslau et al., 2005; Gonzalez et al., 2010),
suggesting a more severe manifestation of the disease. Finally, evidence has
suggested significantly higher rates of depression and suicide in Latino/a/a adolescents,
3
especially females, relative to other groups (Guzman et al., 2009; McCord et al., 2019;
Twenge and Nolen-Hoeksema, 2002).

Characteristics of Depression in Latino/as
Despite having similar prevalence for depression relative to non-Latino/a whites, it is
likely that Latino/as experience a more disabling form of depression. Depressed
Latino/as show greater chronicity (Gonzalez et al., 2010) (see above) and, in some
cases, greater functional impairment compared to Whites (Lopez et al., 2018) (although
see (Lesser et al., 2007)). Likewise, Latino/as report higher rates of somatic symptoms
than non-Latino/a whites (Dunlop et al., 2020; Rao et al., 2012), which is significant
since presence of such symptoms is associated with poorer outcome across numerous
measures (Kapfhammer, 2006). Depressed Latino/as more frequently experience
comorbidity with other psychiatric disorders, including anxiety (Camacho et al., 2015)
and psychosis (Cassano et al., 2013; Cassano et al., 2012).

Treatment Resistant Depression
Despite widespread use, Antidepressant medications (ADM) have limited efficacy, with
approximately 30% of subjects failing to show symptom remission even after several
successive trials with different medications, and another 20 to 30% showing only partial
symptom reduction (Mrazek et al., 2014). The failure to respond to antidepressant
treatment has been termed treatment-resistant depression (TR) and there is currently
great interest in identifying the underlying factors that produce this condition. TR
depression is associated with significantly greater health care utilization and costs,
4
including greater number of emergency room visits, as well as increased economic
burden (Amos et al., 2018; Gibson et al., 2010; Li et al., 2020; Pilon et al., 2019;
Shrestha et al., 2020). Early treatment success is critical since the duration of untreated
depression is associated with poorer outcome once treatment is initiated (Bukh et al.,
2013; Kisely et al., 2006). Probability of treatment success likely also decreases as a
function of prolonged failed treatment with an ADM. Both duration of untreated illness
and treatment-resistance have been linked to reduced hippocampal volume (Sheline et
al., 2003; Videbech and Ravnkilde, 2004)
Several studies have sought to determine factors that predict TR (Bennabi et al.,
2015; Fabbri et al., 2020; Kautzky et al., 2019; Yang et al., 2019), but these have
typically focused on clinical or biological variables and have tended to focus less on the
role of social and environmental factors, which may play an especially important role in
underserved populations. Identification of predictors of TR would be helpful and could
aid in early identification of treatment non-responsive patients, allowing physicians to
quickly direct patients to more aggressive therapies thereby limiting the potentially
irreversible consequences of untreated depression.

Treatment Resistance in Latino/as
Few studies to date have addressed the prevalence or etiology of TR depression in
Latino/as. This aligns with the paucity of studies addressing minority health in general
and suggests a much-needed focus for increased study. Two central issues need to be
considered when assessing the effectiveness of standard ADMs in Latino/as. First,
Latino/as in general have a number of barriers to adequate depression care, including
5
lower probability of having health insurance, linguistic barriers, immigration status,
transportation and employment (Alegria et al., 2002; Alegria et al., 2008b; Kim et al.,
2011; Wells et al., 2013) Even when Latino/as have access to mental health care
resources, they are still less likely to be given a diagnosis of depression or be
prescribed ADMs than non-Latino/a whites (Lagomasino et al., 2011; Shao et al., 2016).
These considerations suggest lower levels and quite likely different patterns of exposure
to ADMs compared to non-Latino/a whites. A second difficulty in assessing treatment
resistant depression in Latino/a populations is the relatively low rate of acceptance and
tolerance of ADMs relative to non-Latino/a whites. Latino/a Americans show lower rates
of treatment adherence for traditional ADM compared to the general population (Olfson
et al., 2006; Vargas et al., 2015; Warden et al., 2009). Numerous factors have been
suggested to account for lower adherence, including concerns about the addictive
potential of ADMs, concerns about adverse effects, preferences for non-medicinal
treatments, concerns about maintaining access to medications, and stigma associated
with ADMs (Dwight-Johnson et al., 2010; Green et al., 2017; Interian et al., 2007;
Vargas et al., 2015; Wells et al., 2013) . Studies of TR depression in this population
need to carefully consider how these factors affect success of treatment and apparent
treatment-resistance when assessing the effectiveness of ADMs.

Current Evidence for Treatment Resistance in Latino/as
While no studies have formally assessed the prevalence of TR depression in Latino/as,
extant literature suggests a similar prevalence relative to non-Latino/a whites.
Examination of data from the NIMH STAR*d study found no difference in remission rate
6
or time to reach remission between Latino/a and non-Latino/a White subjects treated
with citalopram (Lesser et al., 2007). African Americans were slower to reach remission
but had higher baseline depression severity compared to Latino/as and Whites. After
adjusting for baseline depression, socioeconomic and demographic levels, change
following treatment was similar across groups on the Hamilton Rating Scale for
Depression, but was still lower for blacks on the QIDs (Lesser et al., 2007). No
differences were found in response to Paroxetine in a double-blinded clinical trial
between Latino/a and White, Black or Asian groups, although Latino/a patients showed
a higher placebo effect (Roy-Byrne et al., 2005). A study that included low income
(predominantly poor or near poor) Latinas born in Latin America showed that Paroxetine
(or Bupropion) significantly reduced depression symptoms when compared to Latinas
referred to community care (Miranda et al., 2003a). Medication was similarly effective in
Latina subjects, low-income White and African American women. Latino/a patients
showed increased response to practice-initiated quality improvement interventions that
included both psychotherapy and medication compared to standard care (Miranda et al.,
2003b). Interestingly, both Latino/a and African Americans showed greater response to
the improved intervention than did Whites but showed less response to standard care
than Whites. Likewise, in a study of older depressed patients, Latino/as showed similar
improvement in depression outcome compared to Blacks and Whites following a
collaborative care program that included antidepression medication of psychotherapy
(Arean et al., 2005).

7
The studies cited above do not show any obvious reduction in treatment
response in Latino/as compared to other groups, suggesting that the level of TR
depression could be similar across Latino/as and non-Latino/a Whites. However, there
are important limitations to these studies. Roy-Byrne, et al, (2005) did not differentiate
between White and non-White Hispanics (Roy-Byrne et al., 2005) and only looked at
one ADM. The STAR*D study was not double blinded and only included White
Hispanics (Lesser et al., 2007). Miranda, et al 2003b, only looked at female patients.
None of these studies looked at response as a function of Latino/a subgroup. Further,
none of these studies were conducted specifically to determine prevalence or incidence
of treatment-resistant depression in Latino/a patients.

8
Chapter 2: Factors that predict Treatment Resistance

In lieu of studies that have specifically addressed treatment-resistance in Latino/a
patients, it is useful to identify the factors that have been associated with treatment-
resistance in other populations and then assess the degree to which these factors are
present in Latino/a populations. A broad range of factors have been suggested to be
linked to treatment-resistance. Most of these studies were conducted in non-Latino/a
Caucasian populations. As such, it is likely that there are risk factors for treatment-
resistance that may be unique to Latino/as and/or other non-White populations,
including discrimination and acculturation.

Social – Environmental
Early Life Stress/Adverse Childhood: The Centers for Disease Control defines Adverse
Childhood Events as potentially traumatic events that occur in childhood (0-17 years)
(https://www.cdc.gov/violenceprevention/aces/fastfact.html?CDC_AA_refVal=https%3A
%2F%2Fwww.cdc.gov%2Fviolenceprevention%2Facestudy%2Ffastfact.html), and can
include violence, physical or emotional neglect. Adverse Childhood Experiences (ACE)
are associated with approximately 45% of childhood-onset and 30% of adult-onset
psychiatric disorders (McLaughlin et al., 2010). The effects of ACE exposure on most
outcomes appears to be cumulative, as it is the number of ACE exposures rather than
the type that appears to matter most for negative outcomes (Felitti et al., 1998).
Individuals exposed to 4 or more ACEs are 4.7 times more likely to develop depression
and 37.5 times as likely to attempt to commit suicide (Hughes et al., 2017). ACE
9
exposure likely contributes to the development of depression through a variety of
pathways, including alteration of HPA axis function (Heim et al., 2008; Tarullo and
Gunnar, 2006), epigenetic changes (McEwen, 2012) and by altering brain development
(Teicher et al., 2003).
Exposure to ACEs is associated with a poorer response to antidepressant
medication. Zisook, et al., (2019) looked at veterans that failed to respond to a current
antidepressant (>16 on Qids after 6 weeks of treatment). Patients who failed to remit
had greater numbers of ACEs than those who reached remission (Zisook et al., 2019).
Similarly, clinically significant abuse has been associated with reduced probability of
reaching remission following antidepressant treatment (Klein et al., 2009). As well,
emotional and physical abuse lengthened the amount of time needed to achieve
remission and greater likelihood of requiring combined treatment (to reach remission
(Miniati et al., 2010). Finally, ACE exposure has been linked to increased likelihood of
receiving treatment augmentation (Kim et al., 2013).
Several studies have identified increased exposure to ACEs in Latino/as (Giano
et al., 2020; Gilbert et al., 2015; Klein et al., 2009; Llabre et al., 2017; Merrick et al.,
2018). For example, 77.2% of Latino/as had experienced at least one ACE and 28.7%
had experienced 4 or more ACEs (Llabre et al., 2017), which is considerably higher
than the general population(Giano et al., 2020). ACE exposure is higher in persons born
in the US compared to those born outside of the US (Llabre et al., 2017). Thus, actual
ACE exposure in Latino/as may be higher than that reported in extant studies, as the
nature and number of ACEs in Latino/as may differ from other populations. Further, no
studies have assessed ACE experience in Latino/as using specialized instruments
10
designed specifically for this population. Prevalence of Aces also differs across SES,
with lower SES associated with higher ACE exposure (Giano et al., 2020). As many
Latino/as are in lower SES categories, and may be less likely to be included in studies,
there may be a subset of Latino/as at significantly higher risk of ACE exposure that has
not been captured in extant studies.
How ACE exposure contributes to treatment-resistance remains unclear. ACE
exposure is related to earlier onset of depression, greater number of episodes, and
greater episode duration (Klein et al., 2009; Kornstein and Schneider, 2001; Miniati et
al., 2010; Nelson et al., 2017; Tunnard et al., 2014), all of which have been linked to
treatment-resistance (Bennabi et al., 2015; Dudek et al., 2010; Kautzky et al., 2019).
Additionally, studies have shown higher rates of neuro-vegetative symptoms in persons
with a history of childhood adversity compared to those without (Harkness and Monroe,
2002; Levitan et al., 1998; Miniati et al., 2010). Likewise, suicide is higher in depressed
people with high ACE exposure than those without (Sahle et al., 2021; Thompson et al.,
2019). This suggests that ACE exposure may simply lead to a more severe form of
depression that is less amenable to treatment via medication. Alternatively, ACE
exposure may lead to significant health co-morbidity that impacts depression severity
that is not addressed by ADMs (Hughes et al., 2017).

Discrimination: One in four Latino/as report experiencing discrimination due to ethnicity,
race or language use (https://www.pewresearch.org/hispanic/2018/10/25/Latino/as-and-
discrimination/), as well as color. While several studies have linked discrimination with
depression prevalence and/or symptom severity in Latino/as (Finch et al., 2000; Kwon
11
and Han, 2019; Meca et al., 2020), there are no studies that have assessed the impact
of discrimination on response to ADM medication or TR. Discrimination is linked several
factors associated with TRD in other populations, especially increased stress (Berger
and Sarnyai, 2015; Pascoe and Smart Richman, 2009).

Acculturative stress: Latino/as who immigrate to the United States face substantial
pressure revolving around cultural identity which generally centers upon the degree to
which they adopt mainstream US culture (Anglo orientation) and maintain connection to
their cultural heritage (Latino/a orientation) (Torres, 2010). Studies have shown that
pressures due to cultural identity are positively linked to depression. Specifically, Anglo
orientation is positively correlated with depression, while Latino/a orientation appears to
provide protection against depression (Torres, 2010). Cultural pressures are especially
intense during adolescence, which may contribute to increased rates of depression in
Latino/as during this time (Cano et al., 2015; McCord et al., 2019; Stein et al., 2012).
Assessment of the link between acculturative stress and response to ADMs is complex,
as partaking in mainstream psychiatric practices is likely dependent upon the adoption
of an Anglo orientation. Nonetheless, the effect of acculturative stress on response to
depression medications does not appear to have been assessed in formal study.

Other: Numerous environmental factors disproportionally experienced by some
Latino/a/as, including poverty, food insecurity, exposure to violence, immigration status,
community safety, exposure to environmental pollutants, are likely linked to response to
ADMs but do not appear to have been addressed.
12
Psychiatric Co-morbidities
Anxiety: Co-morbid anxiety has been liked to treatment resistant depression across
multiple studies (Diefenbach et al., 2013; Ionescu et al., 2014; Kautzky et al., 2019;
Lydiard and Brawman-Mintzer, 1998; Souery et al., 2007; Zisook et al., 2019). “Anxious
depression”, defined as MDD with high levels of anxiety, was associated with lower
rates of remission in the STAR*D trial (Fava et al., 2004; Fava et al., 2008; Zisook et al.,
2019) and is more prevalent in patients who are treatment resistant (Wu et al., 2013). In
a study of 16,064 participants, approximately 10% of Latino/as showed high levels of
anxious depression, while a further 30% showed moderate levels (Camacho et al.,
2015). This was highest in Latino/as from a Puerto-Rican background (Camacho et al.,
2015). It is not clear how this compares to non-Hispanic Whites or other non-Latino/a
groups.

Bipolar Features: Patients diagnosed with Major Depressive Disorder that scored high
on the Mood Disorder Questionnaire or Hypomania checklist, but who did not meet the
criteria for a diagnosis of Bipolar Depression, were more likely to be treatment-resistant
than those who showed fewer bipolar features (Dudek et al., 2010). Sharma, et al
(2005), found that a majority of patients with major depressive disorder in a hospital
setting met the criteria for either Bipolar II or Bipolar Spectrum, suggesting possible
misdiagnosis (Sharma et al., 2005). These findings received mixed support in the
Star*D study. Here, 38.1% of treatment-resistant depressed subjects showed at least
one bipolar like symptom (mania/hypomania) on the Psychiatric Diagnosis Screening
Questionnaire (Perlis et al., 2011). However, such symptoms did not significantly predict
13
outcome of subsequent treatment with citalopram (Perlis et al., 2011), suggesting that
bipolar features are not significantly linked to treatment-resistance. In a similar vein,
agitated “unipolar” depression, which is characterized as negative affect with increased
activity (restlessness, increased talkativeness, irritability, etc.), has been suggested to
be linked to reduced response to ADM treatment, as well as heightening of agitated
characteristics (Sampogna et al., 2020). To date, no studies appear to have addressed
the prevalence of agitated or mixed depression in Latino/a/as. Interestingly, the
constellation of features associated with this type of depression shares some overlap
with the concept of ‘nervios’ (Guarnaccia et al., 2003).

Psychotic features: In Psychotic Depression or Major Depression with Psychotic
Features, individuals experience hallucinations and delusions in addition to symptoms
of depression (Coryell, 1996). Psychotic depression is associated with greater symptom
severity and poorer prognosis(Coryell, 1996). Importantly, psychotic depression is
associated with increased treatment-resistance (Dold et al., 2019), and is usually only
successfully treated with combined antidepressant/antipsychotic medication. Two
studies have shown increased rates of psychotic depression in Latino/as compared to
non-Latino/a Whites (Gaudiano et al., 2009; Posternak and Zimmerman, 2005).

Biological
Biological explanations for treatment-resistance have centered upon potential
differences in drug metabolism rates, deficits in neurotransmitter systems, especially
serotonin, associated with SSRI response, HPA-dysregulation, deficiencies in BDNF
14
(El-Hage et al., 2013). Ultra-rapid drug metabolizers have been identified based on
variations in CYP related genes that show greatly reduced response to ADMs (El-Hage
et al., 2013). In contrast, poor metabolizers may show increased side effects and
ultimately a poorer response to ADM. Few studies have assessed pharmacogenetics in
Latino/as. CYP2D6 has been shown to influence response to ADM and may be slightly
altered in Mexican Americans (Mendoza et al., 2001). However, this has not specifically
been addressed in a formal study involving ADM. Likewise, little data exists regarding
differences in serotonin function, HPA-dysregulation or BDNF in Latino/a versus non-
Latino/a groups.

Developing a model of TRD in Latino/as
The issue of treatment resistance to ADM in underserved communities is one of great
importance but has received little attention. As such, it is difficult to identify the factors
that underly, and which could be used to predict, treatment-resistance in this group.
Since little is known about TRD in Latino/as we need to rely on studies from other
populations. As stated above, numerous variables have been shown to be linked to
TRD. However, assessment of all the variables listed above is beyond the scope of a
single study. As such, careful selection of variables is needed. The best variable to
begin with is one that meets the following criteria. First, the variable has been linked to
TR in other populations. Second, the variable is associated with depression severity,
which in itself is related to TRD. Third, the variable is experienced at elevated rates in
Latino/as. Of the variables listed above, early childhood adversity is the only one that
meets all these criteria. The overarching goal of this study is to develop simple model of
15
treatment resistant depression and assess how well it works. Subsequent studies will
then refine this model using additional variables.

Hypothesis: This study will assess the following research question: Does exposure to
adverse childhood events lead to increased risk for treatment resistant depression in
depressed Latinx patients? The hypothesis is that TRD will be elevated in patients who
have experienced significant ACEs.

16
Chapter 3 Methods

Design
This is a single center, case control study. Cases consist of depressed Latinx subjects
identified as TR, while controls consist of treatment responsive depressed Latinx
subjects, with TR determined via the Maudsley Staging Method. A total of 51 subjects
were recruited from the LAC+USC adult outpatient clinic. Recruitment occurred over the
first year of the award period. Both male and female subjects participated in the study.
Patients were identified using electronic medical records and by recommendation of
clinicians in the LAC-USC adult outpatient psychiatric clinic. Subjects were adults, 18 to
60, who had a primary diagnosis of major depression, and who were of Latino heritage.
Subjects were excluded if they meet the criterion for other psychiatric disorders
(delusional disorder, bipolar depression, schizophrenia). Final eligibility was determined
based on responses provided via screening instruments that were given during the as
part of the interview (see discussion below for details).

Interview
Participants were contacted by phone by a study team member to determine their
willingness to participate in the study. During this phone call they were told: 1) what they
study required them to do 2) the main question the study was attempting to answer 3)
the risks of participating in the study 4) the length of time needed to complete the study
as well as the number of study visits 5) that they could withdraw from the study at any
time for any reason and 6) that they would receive $40 payment as compensation for
17
participating. If the participant agreed to take part in the study, they were sent a link to
an online informed consent form and a HIPAA authorization form. A time was then set
during which the interview would take place.
During the interview, subjects were first asked complete a series of questions
relating to demographic information. This included questions about Age, Gender, Marital
Status, Years of Education, and Income, Acculturation. These questions were placed at
the beginning in order to ease participants into the interview. If subjects were later
excluded from the study, this information was destroyed. Confirmation of depression
diagnosis and assessment of severity was determined by administration of the PHQ-9,
which queries 9 items relating to depressive symptoms, each of which is ranked by the
participant according to 4 categories of frequency of occurrence (not at all, several
days, more than half the days, or nearly every day). Scores can range from 0 to 27, with
scores of 5 or more indicating likely depression. The Suicide item from the PHQ-9,
which asks whether the patient has experienced “Thoughts that you would be better off
dead, or thoughts of hurting yourself in some way?” was used to assess previous
suicide attempts. If the patient answers “several days” or greater, further questions are
asked including whether they had previously attempted suicide. Note that only those
individuals who are previously having suicidal thoughts will be asked about previous
attempts. As such, this measure could be under-estimating suicide attempts. Subjects
then received two items designed to assess bipolar depression and schizophrenia,
respectively, the Mood Disorder Questionnaire (MDQ) and Psychotic Symptom Scale.
Subjects were excluded if they did not have major depression (n=1), or if their
responses indicated the presence of bipolar depression (n=1) or schizophrenia (n=2).
18
The remaining survey items consisted of the following. Co-Morbid Medical Illness: The
item lists several medical conditions with increased prevalence in Latinos, such as
diabetes, high blood pressure, obesity, etc., as well as questions about inflammatory
diseases (psoriasis, lupus, arthritis). These latter items were added based on reports of
an association between inflammatory diseases and depression. Antidepressant
Adherence Scale: This is a 4-item scale which assesses how well patients adhere to a
medication regimen (forgetting, carelessness and stopping medication). Perceived
Stress Scale: A ten item measure that assesses the experience of stress, including
feelings of being overwhelmed by stressful events and being unable to control stressful
events. Lubben Social Network Scale: This scale measures size of social network
separately for both family and friends. It consists of 12 questions (6 for family and 6 for
friends), which are as follows: How many relatives/friends do you see or hear from at
least once a month? How often do you see or hear from the relative/friend with whom
you have the most contact? How many relatives/friends do you feel at ease with that
you can talk about private matters? How many relatives/friends do you feel close to
such that you could call on them for help? When one of your relatives/friends has an
important decision to make, how often do they talk to you about it? How often is one of
your relatives available for you to talk to when you have an important decision to make?
Scores for each item can range from 0 (no friends) to 5, for a total of 30 points. Adverse
Childhood Events Scale: This scale was created by the Center for Disease Control to
retrospectively assess level of adverse events experienced prior to the age of 18. A total
of 10 categories of adverse event are queried: physical abuse, sexual abuse, verbal
abuse, emotional neglect, physical neglect, parental divorce, incarcerated household
19
member, mentally ill or suicidal household member, substance abusing household
member, witnessing domestic abuse. Generalized Anxiety Disorder 7 (GAD-7): This is a
standard scale used to assess presence of generalized anxiety disorder and consists of
7 items. Panic Disorder Severity Scale: Assesses whether the subject suffers from
panic disorder or panic attack. The Pandemic Stress Index, which assess level of
distress related to the Covid-19 pandemic. The Daily Discrimination Index, which
assesses exposure to minor events perceived to be discriminatory.

Maudsley Staging Method
After the interview was complete, participants were reminded of the possibility of an
additional phone call. However, completion of the Maudsley was primarily done through
chart review, as participants often lacked detailed knowledge about some aspects of
previous treatments, etc., making chart review more reliable. The Maudsley Staging
Method ranks treatment-resistance according to three criteria: Depression Duration,
Symptom Severity, and Past Treatment Failure. Duration refers only to the duration of
current depression episode, and is ranked as Acute (< 12 months, 1 point), Sub-Acute
(13 to 24 months, 2 points) and Chronic (> 24 months, 3 points). Symptom severity was
ranked as sub-syndromal (no depression, 1 point), mild (PHQ-9 score between 5 – 9, 2
points), moderate (PHQ-9 score between 10 and 19, 3 points), severe (PHQ-9 score
above 20, 4 points). Instructions for the Maudsley suggest scoring severe depression
with psychosis as a 5. However, psychotic patients were excluded from the study.
Treatment failure was scored based on the number of antidepressants used
unsuccessfully at an adequate dose for a duration of at least 6 weeks and ranged from
20
1-2 medications (1 point), 3-4 medications (2 points) up to greater than 10 medications
(5 points). An extra point was given if augmentation had been used (typically another
antidepressant or medication) and an additional point was given if the patient had tried
ECT. Scores on the Maudsley can range from 3 to 15, with scores from 3 to 6 classified
as mild, 7 to 10 as moderate and scores from 11 to 15 as severe treatment-resistance.
Patients were classified as responsive if they scored less than 3, which could occur if
the person was sub-syndromal (1 point), had an acute duration (1 point) but had
responded to previous treatment (0 points0>

Statistical Analyses
Details about statistical analyses are listed in their respective results section.

21
Chapter 4: Results

Demographic information
Participants were predominantly female (80.4%), unemployed (69.9%), with a mean age
of 42.5 years (SD 13.3), and of Mexican descent (82.7%). The majority of participants
were non-US born (53.8%) with an average length of residency in the US of 30 years
(SD 13). 67.3% conducted the interview in English. See table 1 for details.

Table 1 N (51 Total) %
Age 42.5 ± 13.3
Gender
Female 41 80.4
Male 10 19.6
Other 0 0
Non-US Born 28 53.8
Ancestry
Mexico 43 82.7
El Salvador 5 9.6
Guatemala 2 3.8
Puerto Rico 1 1.9
Spanish Interview 17 32.7

Full or Part Time
Employed
16 30.1
Education
High School or less 25 49
> High School 26 51
Marital Status
Single Never Married 22 43.1
Divorced 8 15.7
Married Now Living w
Partner
21 41.2

22
Clinical Characteristics
The average number of ACEs experienced was 5.1 (SD 2.9), with 64.7% of participants
reporting exposure to 4 or more ACEs. In terms of specific ACEs, exposure to emotional
neglect and verbal abuse were experienced by a majority of participants, while sexual
abuse, domestic violence and physical neglect were experienced by less than half. The
mean PHQ-9 was 13.47, (SD 7.6), suggesting moderate depression. Mean perceived
stress was 21.7 (SD 8.3), which is also in the moderate range. Participants reported on
average 3.5 co-morbid health conditions and the majority (60.7%) were treatment
resistant. Lubben family network was mean 18.1 (SD = 5), while social network was
11.8 (SD = 7.7) (see table 2 for details).
Table 2
N =51 N/Mean %/SD
ACE 5.1 2.9
>= 4 ACEs 33 64.7
Ace Category
Verbal Abuse 35 68.6
Physical Abuse 30 58.8
Sexual Abuse 22 43.1
Emotional Neglect 37 72.5
Physical Neglect 23 45.1
Divorce 28 54.9
Domestic Violence 21 41.2
Alcoholic Parent 27 52.9
Mental Illness 22 43.1
Incarcerated Fam 16 31.4
PHQ-9 13.5 7.6
Perceived Stress 21.7 8.3
Co-morbid Health 3.5 2.4
Maudsley
Responsive 21 42
Resistant 29 58
Lubben Social Network
Family 18.1 5
Friend 11.8 7.7

23
Primary Analysis
Logistic regression was used to assess the relationship between ACE exposure (0 to
10) and treatment response (yes or no). ACE exposure was not significantly associated
with being treatment resistant (OR = 1.07, 95% CI 0.88, 1.3, p = 0.51). Due to the
relatively small number of participants at each ACE level, a further Logistic Regression
analysis was conducted which categorized ACE score as a binary variable using scores
of less than 4 (n=18) versus 4 or greater (n=33) as a cutoff. This was also not significant
(OR = 1.7, 95% Ci 0.52, 5.4, p = 0.39).

Secondary Analyses
Suicide: Logistic regression was used to assess the relationship between ACE
exposure (0 to 10) and suicide attempt (yes or no). ACE number did predict previous
suicide attempt (logistic regression: OR = 1.74, 95% Confidence Interval 1.063, 2.9, p =
0.028). The odds ratio for 4 or more ACEs on suicide attempt was 10.5. Since none of
the participants with ACE scores below 4 reported a previous suicide attempt odds ratio
was calculated by adding 0.5 to each cell. This was not analyzed via regression.

Perceived stress: In contrast, perceived stress was significantly associated with being
treatment resistant (OR = 1.08, 95% Confidence Interval 1.001, 1.17, p = 0.047).

24
Country of Birth: Significant differences have often been reported in the literature when
comparing US born and non-US born
Latino/a subpopulations (see above).
Within the current dataset, obvious
differences in age and size of friend
network were apparent between these
groups, suggesting a need for additional analyses. Statistical analyses. For continuous
data an independent t-test was conducted with the outcome of interest as the
dependent and country of birth as the independent variable. Levene’s test was used to
assess homogeneity of variance. In cases of significant departure from homogeneity an
adjusted t-test was used. For count data Pearson Chi Square was used with the
variable of interest as the dependent variable and country of birth as the independent
variable. Only significant results are reported (see table 3 for further information). Non-
US born participants were significantly older than their US born counterparts (t40.8 =
4.54, p<0.001). Non-US born participants had a significantly smaller friend network (t49.
= -2.5, p = 0.017). Non-US born participants were more likely to have experienced
sexual abuse (Pearson X
2
= 4.97, df=1, p=0.026), but less likely to have had an alcoholic
or drug using parent (Pearson X
2
= 4.7, df=1, p=0.031). Non-US born participants were
also less likely to have education beyond high school (Pearson X
2
= 5.3, df=1, p=0.022)
and more likely to have a Spanish language preference (Pearson X
2
= 15.8, df=1,
p<0.001).
Table 3
Non-US born US born P Value
Age (Mean, SD) 49.1 (9.8) 34.5 (12.7) *
Female (%) 78.6 82.6 n.s.
25
Full or PT Employed n%) 25 36.4 n.s.
Co-Morbid Health (Mean, SD) 4.1 (2.4) 2.8 (2.2) n.s.
PHQ-9 (Mean, SD) 14.1 (7.7) 12.7 (7.5) n.s.
Perceived Stress (Mean, SD) 21.9 (8.6) 21.4 (8.2) n.s.
Lubben Friend Network 9.5 (7.6) 14.7 (6.9) *
Lubben Family Network 18.2 (5.8) 18.1 (3.9) n.s.
ACE (Mean, SD) 4.9 (3.2) 5.3 (2.6) n.s.
Verbal Abuse (%) 64.2 73.9 n.s.
Physical Abuse (%) 53.5 65.2 n.s.
Sexual Abuse (%) 57.1 26.1 *
Emotional Neglect (%) 67.8 78.2 n.s.
Physical Neglect (%) 53.5 34.8 n.s.
Divorce (%) 53.5 56.5 n.s.
Domestic Violence (%) 39.3 43.4 n.s.
Alcoholic Parent (%) 39.3 69.6 *
Mental Illness (%) 39.3 47.8 n.s.
Incarcerated Fam (%) 32.1 30.4 n.s.
ACE >= 4 64.3 65.2 n.s.
Suicide Attempt (%) 10.7 17.4 n.s.
Education (N=50)
> Highschool (%) 37 69.5 *
Spanish Interview (%) 57.1 4.3 **
Maudsley
Responsive (%) 37 47.8 n.s.
p < 0.05 *
p < 0.01 **

Social Network and health: 15.3% participants scored 0 on the Lubben friend test and
37.3% scored below 10, suggesting an almost complete lack of friends. This result was
completely unexpected and was deemed to warrant further assessment. Lack of friends
was found to act as a strong predictor of negative health outcome:, especially in regards
to depression severity [PHQ-9: (r
2
= 0.18, F(1,49) = 10.8, p = 0.002)], stress [Perceive
Stress Scale; (r
2
= 0.18, F(1,49) = 3.52, p = 0.067)], number of co-morbid health
conditions (r2 = 0.95, F(1,48) = 5.02, p = 0.03) and treatment response [Maudsley: OR
= 0.88, 95% Confidence Interval 0.79 0.97, p = 0.01)]. Interestingly, almost all
participants showed normal sized family networks with only 5.8% with scores below 10,
26
and 0% with scores of zero. Nonetheless, there was a significant correlation between
family and friend scores (Pearson’s r = 0.31, p = 0.029).

27
Chapter 5: Discussion

ACE scores were high overall, with participants reporting a mean of ACE number of 5.1.
ACEs are typically divided into childhood abuse (sexual, verbal and physical abuse,
emotional and physical neglect) and family dysfunction (divorce, domestic abuse,
incarceration of family member, alcoholic family member, and mental illness in a family
member). The most commonly experience ACEs all belonged in the abuse category,
with emotional neglect the highest ACE (73%), followed by verbal and physical abuse
(69 % and 59%). Household dysfunction ACEs were less commonly reported. Although
the general theory of ACEs states that the particular pattern of ACE exposures matters
less rather than the cumulative effect of multiple ACE exposures, it seems reasonable
to suggest that ACEs in the abuse category are more impactful on psychological health
and well-being than household dysfunction. There was no difference between ACE
scores in US versus foreign born participants. However, a slightly different pattern of
ACE exposures was found between US and foreign born in terms of sexual abuse
(higher in foreign born) and alcoholic family member (high in US born).
Overall, there was no effect of ACE on treatment response. Several explanations
could by put forth to explain this finding. First, standard ACE measures may not fully
capture the range of adverse childhood events in this population. The ACE measure
used in this study and others (ACE questionnaire) was largely developed in a middle-
class, non-Latino Caucasian population who were insured within an HMO (Felitti et al.,
1998). Questions on this survey focus largely on inter-familial events rather than
environmental or community level risk events. As such, this instrument may not fully
28
capture the types of adverse childhood experiences of vulnerable populations, which
are likely to include factors such as unsafe communities, violence and racism. For
example, the standard ACE instrument has been criticized for not including questions
about events that may be unique to Latino experience, such as insecurities associated
with immigrant status (Caballero et al., 2017). Several ACE instruments have been
developed for use in vulnerable populations, including the Philadelphia ACE survey
(Cronholm et al., 2015) and the WHO ACE international questionnaire (ACE-IQ), both of
which include a broader range of experiences, including exposure to gang violence,
foster care, childhood illness, bullying, community violence, immigration status. A study
assessing the Philadelphia ACE measure found 13.9% of respondents who reported
only one of the expanded ACEs and none of the standard ACEs, demonstrating that
standard ACE measures can miss a substantial number of subjects (Cronholm et al.,
2015). Expanded ACE surveys do not appear to have been used within the context of
mental illness and Latino/as. Secondly, it is possible that Latino/as experience
significant adult stress (adverse adult events) which might play a more important role or
may be more severe than adverse events experienced in childhood. For example, two
participants reported having been shot as adults, one participant had been the victim of
an attempted murder by a boyfriend, and one participant had seen his father murdered
as an adult. This may explain the significant effect between adult stress and treatment
response. Unfortunately, relatively little attention has been focused on the impact of
adult stress and/or trauma psychiatric outcome in general and treatment response in
particular. Future studies should play more attention to the role of adult stress. Third,
the Maudsley may not be a useful measure in under-resourced Latino/as. A significant
29
component of treatment response is the number of past treatment failures, which might
be meaningful in a minority group with significant treatment barriers and lack of care.
Likewise, receiving severe score on the Maudsley requires having had
augmentation of treatment, usually additional medications, or electro convulsive
therapy, both of which are often not widely used in Latinos. As such, the Maudsley may
significantly overestimate treatment response. Finally, the small sample size may have
made detection less likely and excluded inclusion of potential moderators and
mediators.
Given that reporting of ACEs may be uncomfortable, distressful, or
embarrassing, there is a possibility that some participants may have under-reported
their level of ACE exposures. This could explain why sexual abuse rates were
considerably lower than other abuse ACEs. While it is impossible to rule this out, it
seems likely that under-reporting did not occur at significant levels and therefore is
unlikely as an explanation for the lack of relationship between ACE levels and treatment
response. First, ACE scores were generally high, suggesting if under-reporting did
occur it was not done by many participants. Second, ACE scores were highly related to
previous suicide attempt and none of the participants with ACE scores below four
reported a previous suicide attempt.
A significant positive effect was seen for ACE score and past suicide attempt,
suggesting that high ACE exposure is a significant risk factor for suicide. The observed
odds ratio was 1.74 when considering ACE as a continuous variable, and 10.5 when
assessing the effect of ACE scores of 4 or more. These data provide support for the
importance of ACE exposure in regulating suicide in depressed Latina/os, but also
30
suggest that the link between ACE exposure and suicide may not be as strong in this
group as in other populations. For example, a systematic review assessing 253,719
patients found an odds ratio of 37.5 for the effect of ACE on suicide attempt in the
general population(Hughes et al., 2017). This reduced effect could reflect an increased
importance of adult events compared to childhood events on suicide risk or use of an
ACE measure that misses many significant ACEs experienced in this population. The
reduced effect of ACE exposure on suicide in this population could also suggest greater
resilience and/or resources that individuals draw upon to buffer against the effects of
ACE exposure. Much emphasis has focused on resilience and coping as processes that
buttresses against the effects of ACE exposure (Bethell et al., 2014). Resilience refers
to interpersonal and/or community resources or processes that limit the impact of stress
and adverse events, and can include protective factors, such as having a close
relationship with other caring adults, social connections, and psychological factors.
Primary evidence for the importance of resiliency process comes from the fact that
many people with high ACE exposure do not go on to develop mental illness. Resilience
has been shown to act as a mediator between ACE exposure and depression outcome,
with depression being less severe in people who show high resiliency (Poole et al.,
2017). While evidence supports the role of resilience as a mediating factor in vulnerable
populations, including Latino/as (Bartoszek et al., 2020; Scott et al., 2015), few studies
appear to have addressed resilience or coping strategies in depressed Latino/a
individuals, especially within a community mental health clinic setting or within the
context of suicide.
31
A striking finding was the relatively lack of friends in a significant number of
participants, especially those who were foreign born. Interestingly, this was not found
for family network size, which seemed robust. Increased isolation has frequently been
reported in Latino/a populations, wherein it has been linked to several negative
psychiatric outcomes (Hurtado-de-Mendoza et al., 2014; Ryan et al., 2021). Isolation
within Latino/a immigrant populations has been suggested to be due to inexperience
with US culture, limitations based on occupational characteristics and fear of leaving
their homes because of immigration enforcement. In the current population, low friend
network was associated with depression severity, treatment response, stress
experience and number of co-morbid health conditions. Indeed, social network size was
a much better predictor of treatment response than the level of ACE exposure. While it
is difficult to establish cause and effect, interventions aimed at increasing friend size
could prove useful in reducing severity of illness in this population.
There are several limitations to this study. First, the sample size was relatively
low. It is possible that we would have detected a significant relationship between ACE
score and treatment response with a larger sample. Moreover, the low sample size
precluded use of a more complete statistical model comprising potential confounding or
moderating variables, such as age, education or country of birth. However, the study is
still ongoing, and the expectation is that the sample size will eventually be sufficient for
such a model. Second, we used a standardized interview to administer the
questionnaires, largely due to expected literacy deficiencies in a subset of participants.
Many of the surveys used were designed to be self-completed, which is less subject to
biases and interviewer idiosyncrasies that could influence participant response. Finally,
32
the study sample was highly skewed towards female participants, with a ratio of 1:4 for
males: females. While depression is more common in females, reported ratios are
closer to 1:2 (Albert, 2015). This may reflect increased stigma associated with being
depressed in Latino men, such that fewer males seek treatment. If so, programs aimed
at increasing mental health treatment in Latino males seems greatly needed.

Conclusion
Few studies have assessed treatment resistant depression in vulnerable groups. Data
reported here showed that adult stress experience was positively associated with both
treatment failure and depression severity in a lower-income, uninsured, primarily Latinx
population. Future studies will address the causal direction of this relationship. ACE
exposure was not associated with treatment failure. The ACE measure used in this
study (ACE questionnaire) was largely developed within an affluent, middle class, non-
Latinx Caucasian population and may fail to adequately capture the experiences of
vulnerable populations. Likewise, adult adverse experiences may play a stronger causal
role in vulnerable populations.

33
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Asset Metadata

Creator Featherstone, Robert Earle (author)

Core Title Understanding anti-depressant treatment failure in an underserved vulnerable population

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Degree Conferral Date 2022-08

Publication Date 07/18/2022

Defense Date 07/18/2022

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag adverse childhood event,Depression,Latinx,OAI-PMH Harvest,Stress,Suicide

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Patino-Sutton, Cecilia (committee chair), Lagomasino, Isabel (committee member), Siegel, Steven (committee member)

Creator Email featherr@usc.edu,refeatherstone@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC111372257

Unique identifier UC111372257

Legacy Identifier etd-Feathersto-10850

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Rights Featherstone, Robert Earle

Type texts

Source 20220719-usctheses-batch-955 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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