Received: 30 April 2020 | Revised: 6 August 2020
DOI: 10.1002/da.23095
RESEARCH ARTICLE
Association of anger attacks with suicidal ideation in adults
with major depressive disorder: Findings from the EMBARC
study
Manish Kumar Jha1,2 | Maurizio Fava3 | Abu Minhajuddin2 | Cherise Chin Fatt2
David Mischoulon3 | Christina Cusin3 | Madhukar H. Trivedi2
1
Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, New York,
New York, USA
2
Department of Psychiatry, Center for
Depression Research and Clinical Care, UT
Southwestern Medical Center, Dallas,
Texas, USA
3
Department of Psychiatry, Massachusetts
General Hospital, Boston,
Massachusetts, USA
Correspondence
Madhukar H. Trivedi, Department of
Psychiatry, Center for Depression Research
and Clinical Care, UT Southwestern Medical
Center, 5323 Harry Hines Blvd, Dallas, TX
75390‐9119, USA.
Email: madhukar.trivedi@utsouthwestern.edu
Funding information
National Institute of Mental Health (NIMH),
U.S. Department of Health and Human
Services, Grant/Award Numbers:
U01MH092221, U01MH092250; Hersh
Foundation
Depress Anxiety. 2020;1–10.
| Accepted: 9 September 2020
|
Abstract
Background: This report evaluates whether anger attacks (sudden uncharacteristic
bouts of anger that are associated with autonomic arousal and/or aggression) in
patients with major depressive disorder (MDD) are associated with elevated suicidal
ideation (SI; active suicidal thoughts and plans).
Methods: Participants of Establishing Moderators and Biosignatures of Anti-
depressant Response in Clinical Care (EMBARC) study who completed Massachu-
setts General Hospital Anger Attack Questionnaire (AAQ) at baseline were included
(n = 293). Levels of SI (suicidal thoughts factor of Concise Health Risk Tracking)
were compared at baseline with generalized linear models, and during Stage 1
(baseline‐to‐week‐8) and Stage 2 (week‐8‐to‐week‐16) with repeated‐measures
mixed model analyses. Covariates included age, sex, race, ethnicity, site, and
treatment arm.
Results: At baseline, participants with (n = 109) versus without anger attacks
(n = 184) had higher levels of SI (Cohen's d effect size [d] = 1.20). Those with ≥9
anger attacks in the past month had significantly higher SI than those with 1–2
(d = 1.21), 3–4 (d = 1.48), and 5–8 (d = 0.94) anger attacks in the past month. Fur-
thermore, participants with anger attacks at baseline reported higher SI at each
post‐baseline visit (both Stages 1 and 2) of EMBARC study (d = 0.39–0.77; all
p < .05). Associations between anger attacks and SI were significant even after
controlling for irritability, hostility, anxious arousal, depression, suicide propensity,
and self‐reported pain at baseline and lifetime suicidal tendencies. Similar results
were found in participants with aggressive behaviors.
Conclusion: Anger attacks in outpatients with MDD may be associated with
chronically elevated SI.
Clinical Trials Registration: Establishing Moderators and Biosignatures of Anti-
depressant Response for Clinical Care for Depression (EMBARC); NCT01407094;
https://clinicaltrials.gov/ct2/show/NCT01407094.
KEYWORDS
anger attack, antidepressant treatment, irritability, major depressive disorder, suicidality
wileyonlinelibrary.com/journal/da © 2020 Wiley Periodicals LLC | 1
2 |
1 | INTRODUCTION
Suicide‐related mortality in the United States has increased by over
35% in the past two decades (Curtin & Hedegaard, 2019; Steelesmith
et al., 2019). Hence, there is an urgent need to identify clinical fea-
tures that are associated with elevated suicide risk. Recent reports
suggest that the presence of anger may be one such feature. Cross‐
sectional studies have reported significant association between an-
ger and suicidality in community samples (Jang et al., 2014) including
in home‐dwelling elderly (Zhang et al., 2017), in veterans (Wilks
et al., 2019), and in patients with chronic cancer pain (Racine et al.,
2017), somatoform disorders (Kampfer et al., 2016), and mood or
anxiety disorders (Stringer et al., 2013). Similarly, longitudinal studies
have also reported an association between the presence of anger at
index visit and subsequent suicidal ideation (SI), suicide attempt, or
completed suicide (Ducasse et al., 2017; Hogstedt et al., 2018; Start
et al., 2019). These findings of association between anger and sui-
cidality are consistent with the previously reported association of
constructs related to anger such as irritability (Conner et al., 2004;
Jha et al., 2020; Orri, Galera, et al., 2018; Orri, Perret, et al., 2018;
Orri et al., 2019; Pickles et al., 2009) and aggression (Fanning et al.,
2016; McCloskey & Ammerman, 2018) with suicidality. However,
these previous reports have not considered the association between
overt behaviors of anger attacks and suicidality.
As described first by Fava et al., anger attacks are sudden bouts
of anger accompanied by autonomic arousal and/or aggression that
are disproportionate to the situation and uncharacteristic of pa-
tient's usual behavior (Fava et al., 1990). Among patients with MDD,
those with anger attacks report similar levels of depression severity
but significantly higher levels of anxiety, somatization, hostility, and
irritability symptoms than those without anger attacks (Fava et al.,
1993). Furthermore, there is a greater reduction in irritability and
hostility symptoms but not in depressive, anxiety, and somatization
symptoms with antidepressant treatment in those with versus
without anger attacks (Fava et al., 1993; Jha et al., 2020). In a recent
report, we found that adults with MDD and anger attacks had sig-
nificantly higher levels of anxiety, hostility, and irritability but not
depression than those with no anger attacks (Jha et al., 2020). We
also found that 79% of adults with MDD and anger attacks also
reported aggressive behaviors including physically/verbally attacking
people, throwing things around, or destroying objects (Jha et al.,
2020). Taken together, these findings suggest that anger attacks are
associated with increased anxiety, irritability, hostility, and aggres-
sion but not depression. Therefore, studies testing for association
between anger attacks and SI should account for these related
constructs along with those associated with increased suicidality
such as prior history of SI/attempt, hopelessness, pain, and depres-
sion (Beck et al., 1993; Fishbain et al., 2014; Mayes et al., 2020;
Oquendo et al., 2006).
This report is based on an unplanned secondary analysis using a
sample of convenience from the Establishing Moderators and Bio-
signatures of Antidepressant Response in Clinical Care (EMBARC)
study, a double‐blind placebo controlled randomized study of
JHA ET AL.
sertraline versus placebo for 8 weeks (Stage 1) followed for 8 more
weeks (Stage 2) either by continuation of Stage 1 medications for
those who clinically responded or by switch to another medication for
those who did not respond (from sertraline to bupropion sustained‐
release and from placebo to sertraline) (Trivedi et al., 2016).
This study aimed to answer the following specific questions:
1. Is the presence of anger attacks associated with higher levels of
SI at baseline (before treatment initiation)?
2. Is the presence of anger attacks at baseline associated with
higher SI even after acute‐phase antidepressant treatment?
Repeated observations over the course of acute‐phase treat-
ment were used to inform whether the presence of anger attacks is
associated with persistently elevated SI. As anger attacks may occur
without overt aggressive behaviors, additional analyses were con-
ducted to evaluate the association between the presence of overt
aggressive behaviors and SI.
2 | M A T E R I A L A N D ME T H O D S
2.1 | Study design and participants
Participants from the EMBARC study (NCT01407094) were included
in this report. As previously described (Trivedi et al., 2016, 2018),
EMBARC enrolled 309 participants with MDD and 40 healthy con-
trols at four academic sites. Of these 309 participants with MDD, 10
were in a feasibility sample and 3 were randomized but were not
eligible for the study. Of the 296 participants with MDD who were
randomized either to sertraline or to placebo, 3 did not complete the
AAQ at baseline. Thus, the modified intent to treat the sample for this
report includes 293 participants with MDD who were randomized and
completed the AAQ at baseline. Institutional Review Boards (IRB) at
each site (Massachusetts General Hospital, Columbia University,
University of Michigan, and UT Southwestern Medical Center) ap-
proved the study and all participants provided signed informed con-
sent before completing any study‐related procedures. The inclusion
and exclusion have been described previously (Trivedi et al., 2016)
and are listed in detail at https://clinicaltrials.gov/ct2/show/
NCT01407094. Briefly, participants were 18–65 years of age, met
criteria for current episode of MDD on Structured Clinical Interview
for DSM‐IV Axis I Disorders (SCID), scored ≥14 on Quick Inventory of
Depressive Symptomatology score (QIDS‐SR) (Rush et al., 2003) at
both screening and randomization visits, did not meet criteria for any
failed antidepressant trial in current episode based on Massachusetts
General Hospital Antidepressant Treatment Response Questionnaire
(MGH‐ATRQ) (Chandler et al., 2010), and agreed to and were eligible
for all biomarker procedures (electroencephalography, psychological
testing, magnetic resonance imaging, and blood draws). Participants
were excluded if they did not tolerate sertraline or bupropion
in the past, were pregnant/breastfeeding/planning to become
pregnant, were medically or psychiatrically unstable, met criteria for
JHA ET AL.
psychotic/bipolar disorder in lifetime, or substance abuse in the past
2 months, or substance dependence in past 6 months, or were on
prohibited concomitant medications (antipsychotic, anticonvulsant,
mood stabilizers, central nervous system stimulants, daily use of
benzodiazepines or hypnotics, or antidepressants).
2.2 | Treatments
2.2.1 | Stage 1
During Stage 1 of EMBARC, participants were randomized to either
sertraline or placebo in a double‐blind fashion in 1:1 ratio, stratified
by site, in the clinical trial management software. The dose adjust-
ments were made using the principles of measurement‐based care by
evaluating depression severity, side‐effects, and adherence (Trivedi
et al., 2006). Sertraline was started at 50 mg and placebo was started
with a single pill. Dose changes were made in 50 mg or 1 pill incre-
ments on a weekly basis. At the end of 8 weeks, participants who
received a score less than “much improved” on Clinician Global Im-
pression Improvement scale were deemed as non‐responders.
2.2.2 | Stage 2
During Stage 2 of EMBARC, responders to Stage 1 were continued
on their assigned treatment (sertraline or placebo) for an additional
8 weeks. Nonresponders were switched to bupropion‐sustained re-
lease from sertraline and to sertraline from placebo for 8 weeks
during Stage 2.
2.3 | Assessments
2.3.1 | Anger attacks
At the baseline visit only, participants completed the AAQ (Fava
et al., 1990). Using this self‐report questionnaire, participants were
categorized as having anger attacks (per Fava et al., “classified as
having anger attacks if they exhibited the following four criteria over
the previous 6 months: 1) irritability, 2) overreaction to minor an-
noyances, 3) occurrence of anger attacks, at least one of which oc-
curred within the past months, and 4) experience during at least one
of the attacks of four or more of the following: tachycardia, hot
flashes, chest tightness, paresthesia, dizziness, shortness of breath,
sweating, trembling, panic, feeling out of control, feeling like at-
tacking others, attacking physically or verbally, and throwing or de-
stroying objects.”) (Fava et al., 1993). Additionally, participants who
endorsed having anger attacks were asked to report the number of
anger attacks in the past month as follows: 0, 1–2, 3–4, 5–8, and 9 or
more. Those participants who responded with “Yes” to AAQ items
regarding “physically or verbally attacking people” and/or “throwing
things around or destroying objects” were grouped as participants
| 3
with aggressive behavior present while others were categorized as
without aggressive behavior.
2.3.2 | Anxious arousal
The 10‐item anxious arousal factor of the Mood and Anxiety
Symptoms Questionnaire (MASQ) was used to assess somatic
arousal (Wardenaar et al., 2010). Each item of the MASQ has a recall
period of a week and is rated on a 5‐point Likert scale with 1 being
“not at all” and 5 being “extremely” (Wardenaar et al., 2010).
2.3.3 | Irritability
Participants completed the five‐item irritability domain of CAST
scale (CAST‐IRR) as a measure of irritability at each visit. Individual
items included, “I wish people would just leave me alone,” “I feel very
uptight,” “I find myself saying or doing things without think-
ing,” “Lately everything seems to be annoying me” and “I find people
get on my nerves easily.” These items were rated on a 5‐point Likert
scale with responses of “strongly disagree,” “disagree,” “neither agree
nor disagree,” “agree,” and “strongly agree” corresponding to scores
of 1, 2, 3, 4, and 5. Previous reports have found strong psychometric
properties of the CAST‐IRR (Jha et al., 2018; Trivedi et al., 2011).
2.3.4 | Hostility
Using a Visual Analogue of Mood Scales (VAMS) at baseline, parti-
cipants rated their current mood as hostile—friendly on a 250 mm
horizontal lines (Pizzagalli et al., 2008; Trivedi et al., 2016). These
responses were converted on a 100‐point scale with lower scores
indicating more hostile mood.
2.3.5 | SI
Participants completed the 3‐item suicide thoughts factor of the
Concise Health Risk Tracking (CHRT) as a measure of suicidality at
each study visit (Trombello et al., 2019). These items included, “I
have been having thoughts of killing myself,” “I have thoughts about
how I might kill myself,” and “I have a plan to kill myself.” These items
were rated on a five‐point Likert scale with responses of “strongly
disagree,” “disagree,” “neither agree nor disagree,” “agree,” and
“strongly agree” corresponding to scores of 0, 1, 2, 3, and 4 re-
spectively (total score range: 0–12).
2.3.6 | Factors associated with suicidality
Clinicians conducted the structured interview for Hamilton Rating
Scale for Depression (HAMD‐17) to assess depression severity
4 |
(Trivedi et al., 2016). Individual items have 3–5 choices which are
scored from 0 to 2 or 0 to 4 (Hamilton, 1960). After a structured
interview at baseline, clinicians rated the most severe lifetime sui-
cidal tendencies as follows: (1) absent; (2) thoughts of dying, but no
thoughts of suicide; (3) occasional thoughts of suicide, no plans; (4)
often thought about suicide or has thought of a specific method; (5)
had a plan or made a gesture; (6) made preparation for a potentially
serious suicide attempt; and (7) suicide attempt with definite intent
to die or be potentially medically harmful. The 9‐item suicide pro-
pensity factor of CHRT, previously shown to predict future suicidal
events (Mayes et al., 2020), was used at baseline to assesses pessi-
mism, helplessness, perceived lack of social support, and despair
(Trombello et al., 2019). The Pain Frequency, Intensity, and Burden
Scale (P‐FIBS) was used to evaluate self‐reported pain symptoms at
baseline of EMBARC study (dela Cruz et al., 2014).
2.4 | Statistical analysis plan
The analytic sample for this report included all trial participants who
were randomized either to sertraline or placebo and completed the
AAQ at baseline (n = 293). Association of SI with irritability, anxious
arousal, and hostility at baseline were estimated with Pearson cor-
relation coefficient (r). Independent samples t test were used to
compare the levels of SI between participants with and without an-
ger attacks at baseline. Cohen's d were estimated to convey the
magnitude of differences in levels of SI between those with versus
without anger attacks at each visit. The data set was bootstrapped
1000 times to create 95% confidence interval (CI) for Cohen's d
value of differences in levels of SI between those with versus without
anger attacks at each visit. Only in participants with anger attacks,
analysis of variance was used to test whether higher frequency of
anger attacks in the past month (categorized as 1–2, 3–4, 5–8, and ≥ 9)
was associated with higher severity of SI at baseline. Generalized linear
models were used to test whether the associations of anger attacks
and their frequency with SI at baseline were significant, even after
controlling for levels of irritability, anxious arousal, hostility, depres-
sion, suicide propensity score, pain, and lifetime suicidal tendencies.
Separate repeated measures mixed model analysis for each Stage
(baseline‐to‐week‐8 and week‐8‐to‐week‐16) with SI as the dependent
variable along with the presence of anger attack and time‐by‐anger
attacks interactions as key independent variables of interest were used
to evaluate whether the presence of anger attacks at baseline was
associated higher levels of SI during Stage 1 and Stage 2 of EMBARC
after controlling for levels of irritability, anxious arousal, hostility, de-
pression, suicide propensity score, pain, and lifetime suicidal tenden-
cies. Similar analyses were conducted to compare participants with and
without self‐reported aggressive behaviors. All regression analyses
with baseline only data included age, sex, race, ethnicity, and site as
covariates; analyses with post‐baseline visit included treatment arm as
an additional covariate. All analyses were conducted using SAS 9.4 and
threshold of significance was set at p < .05.
JHA ET AL.
3 | RES ULTS
At baseline, 37.2% (109/293) participants met the criteria for anger
attacks within the past 6 months. Of these, 44, 32, 19, and 14 re-
ported 1–2, 3–4, 5–8, and ≥9 anger attacks in past month, respec-
tively. As previously reported (Jha et al., 2020), participants with
anger attacks were similar to those without anger attacks in levels of
depression severity (both clinician‐rated and self‐reported) and in
sociodemographic variables, also see Supplementary Table 1. Ag-
gressive behaviors such as physically or verbally attacking people
and throwing things around or destroying objects were reported by
32.8% (96/293) participants, see Supplementary Table 2 for socio-
demographic features of those with our without aggressive beha-
viors. At baseline, there was a significant correlation of SI with
measures of anxious arousal (r = .24, p < .0001), irritability (r = .60,
p < .0001), and hostile—friendly mood (r = −.33, p < .0001)
Is presence of anger attacks associated with higher levels of SI at
baseline (before treatment initiation)?
Yes. At baseline, levels of SI were significantly higher (Cohen's d
effect size [d]= 1.20; 95% CI: 0.95, 1.49) in MDD participants with
anger attacks (mean CHRT suicidal thoughts = 6.91, SD = 1.82) than
in those with MDD and no anger attacks (mean CHRT suicidal
thoughts = 4.46, SD = 2.15). Furthermore, among those with anger
attacks (n = 109), higher frequency of anger attacks in the past
month was associated with higher severity of SI at baseline, see
Figure 1. Specifically, participants with ≥9 anger attacks (n = 14) re-
ported significantly higher SI than those with 1–2 (n = 44; d = 1.21),
3–4 (n = 32; d = 1.48), and 5–8 (n = 19; d = 0.94) anger attacks. See
Supplementary Table 3 for clinical and sociodemographic features
based on the frequency of anger attacks in the past month.
Presence of anger attacks was significantly associated with
higher SI (β = 1.65, SE = 0.25, p < .0001) even after controlling for
irritability, anxious arousal, hostility, depression, suicide propensity
F I G U R E 1 Severity of suicidal ideation (SI) at baseline in
Establishing Moderators and Biosignatures of Antidepressant
Response in Clinical Care (EMBARC) study participants with anger
attacks (n = 109) based on frequency of anger attacks in past
1 month. SI was measured with Concise Health Risk Tracking suicidal
thoughts factor in the EMBARC study
JHA ET AL.
| 5

score, and pain at baseline and lifetime suicidal tendencies (Table 1).
Similarly, SI levels were higher in participants with ≥9 anger attacks
(F = 4.23, df = 3, 83, p = .008) than those with 1–2 (β = 1.63, SE = 0.50,
p = .001), 3–4 (β = .84, SE = 0.49, p = .09), and 5–8 (β = .79, SE = 0.54,
p = .15) anger attacks even after controlling for irritability (β = .16,
SE = 0.05, p = .002), hostility (β = −.00, SE = 0.01, p = .79), anxious
arousal (β = .04, SE = 0.03, p = .14), depression (β = .00, SE = 0.03,
p = .94), suicide propensity (β = .10, SE = 0.03, p = .001) at baseline,
and lifetime suicidal tendencies (β = .02, SE = 0.08, p = .76).
Is the presence of anger attacks at baseline associated with higher SI
even after acute‐phase antidepressant treatment?
Yes. Participants with anger attacks had higher SI than those
without anger attacks at Week 1 (d = 0.74 [95% CI: 0.49, 1.02]),
Week 2 (d = 0.74 [95% CI: 0.47, 1.05]), Week 3 (d = 0.59 [95% CI:
0.33, 0.88), Week 4 (d = 0.60 [95% CI: 0.35, 0.91]), Week 6 (d = 0.56
[95% CI: 0.35, 0.85]), Week 8 (d = 0.49 [95% CI: 0.24, 0.77]), Week 9
(d = 0.88 [95% CI: 0.50, 1.35]), Week 10 (d = 0.40 [95% CI: 0.10,
0.69]), Week 12 (d = 0.41 [95% CI: 0.11, 0.74]), Week 14 (d = 0.50
[95% CI: 0.18, 0.86]), and Week 16 (d = 0.39 [95% CI: 0.09, 0.69]),
also see Supplementary Figure 1.
In repeated measures mixed model analyses, there was a sig-
nificant time‐by‐anger attack interaction during Stage 1 (F = 3.11,
df = 6, 1308, p = .005) but not during Stage 2 (F = 1.74, df = 5, 805,
p = .12), suggesting that changes in SI during Stage 1 of EMBARC
differed on the basis of anger attacks at baseline. As shown in
Figure 2, there was a greater reduction in SI within the first 2 weeks
in those with anger attacks versus those without anger attacks.
However, participants with anger attacks continued to have elevated
levels of SI than those with no anger attacks throughout treatment
as suggested by a significant main effect of baseline anger attacks
(p < .0001) on levels of SI during both stages of EMBARC (Stage 1:
F = 23.76, df = 1, 249, p < .0001; Stage 2: F = 4.88, df = 1, 204,
p = .028) in mixed model analyses that controlled for irritability, an-
xious arousal, hostility, depression, suicide propensity score, and pain
at baseline and lifetime suicidal tendencies, also see Table 2.
3.1 | Association of SI with aggressive behavior
Levels of SI at baseline were significantly higher (d = 1.12) in MDD
participants with aggressive behaviors (mean CHRT suicidal
thoughts = 6.94, SD = 1.90) than in those with MDD and no ag-
gressive behaviors (mean CHRT suicidal thoughts = 4.61, SD = 2.17).
Presence of aggressive behaviors was associated with significantly
higher SI at baseline (β = 1.65, SE = 0.25, p < .0001) even after con-
trolling for irritability, anxious arousal, hostility, depression, suicide
propensity score, and pain at baseline and lifetime suicidal tenden-
cies. Participants with aggressive behaviors at baseline had sig-
nificantly higher SI during Stage 1 (β = 1.67, SE = 0.28, F = 16.11,
df = 1, 252, p < .0001) and Stage 2 (β = .68, SE = .30, F = 4.22, df = 1,
203, p = .041) of EMBARC even after controlling for irritability, an-
xious arousal, hostility, depression, suicide propensity score, and pain
at baseline and lifetime suicidal tendencies.
4 | DISCUSS ION
Using data from a large sample of outpatients with MDD, we found a
strong association between overt behaviors of anger attacks and
patients’ self‐report of SI. Specifically, depressed patients with anger
attacks had significantly higher SI at baseline than those with no
anger attacks. Further, this difference in the level of SI based on
pretreatment presence of anger attacks persisted even after
16 weeks of antidepressant treatment. These associations between
anger attacks and SI were significant even after controlling for re-
lated constructs such as irritability and hostility or other features
associated with SI such as depression, anxiety, previous history of
suicidal tendencies, pain, and hopelessness. Similar findings
were noted for the presence of aggressive behaviors. Taken to-
gether, these findings suggest that the presence of anger attacks
may identify a sub‐group of depressed patients with persistently
elevated SI.

T A B L E 1 Results of generalized linear

Estimate SE F value df p value
model with CHRT suicidal thoughts at
Presence of anger attacks at baseline 1.65 0.25 44.99 1, 219 <.0001 baseline as the dependent variable
Baseline irritability (CAST‐IRR) 0.24 0.03 49.29 1, 219 <.0001

Baseline anxious arousal (MASQ‐AA) 0.02 0.02 0.71 1, 219 .40

Baseline hostility—friendly VAMS −0.01 0.01 2.66 1, 219 .10

Baseline depression (HAMD‐17) 0.03 0.03 0.96 1, 219 .33

Baseline CHRT suicide propensity score 0.05 0.02 6.00 1, 219 .015

Baseline self‐reported pain (P‐FIBS) 0.03 0.02 2.79 1, 219 .10

Lifetime suicidal tendencies 0.10 0.06 2.30 1, 219 .13

Note: Age, sex, race, ethnicity, and site were included as covariates.
Abbreviations: CAST‐IRR, irritability domain of Concise Associated Symptom Tracking Scale; CHRT,
Concise Health Risk Tracking scale; HAMD‐17, 17‐item Hamilton Depression Rating Scale; MASQ‐AA,
Mood and Anxiety Symptom Questionnaire anxious arousal factor; P‐FIBS, Pain Frequency Intensity
and Burden Scale; VAMS, Visual Analogue of Mood Scale.
6 | JHA ET AL.

F I G U R E 2 Changes in suicidal ideation

with treatment among Establishing
Moderators and Biosignatures of
Antidepressant Response in Clinical Care
(EMBARC) study participants with and
without anger attacks. LS means are least
squares means from repeated measures
mixed model analyses with Concise Health
Risk Tracking (CHRT) suicidal thoughts factor
as the dependent variable and irritability,
anxious arousal, hostility, depression, suicide
propensity score, and pain at baseline,
lifetime suicidal tendencies, treatment arm,
age, sex, race, ethnicity, and site as covariates.
Error bars represent standard error

Findings of this report are consistent with the emerging litera- a 35‐year follow‐up were 2.1 and 2.8 times higher in male Swedish
ture linking anger to suicidality (Ducasse et al., 2017; Hogstedt et al., conscripts with severe anger symptoms versus those with no anger
2018; Start et al., 2019). In a recent report, Hogstedt et al. (2018) symptoms at index visit. Similarly, Start et al. found that presence of
found that likelihood of completed suicide and suicide attempts over anger/aggression in active duty service members was associated

T A B L E 2 Results of separate repeated measures mixed model analyses with levels of suicidal ideation as the dependent variable for Stages 1
and 2 of EMBARC study

Stage 1 (baseline‐to‐week‐8) Stage 2 (week‐8‐to‐week‐16)

F value (df) p value F value (df) p value

Baseline irritability (CAST‐IRR) 36.96 (1, 246) <.0001 16.09 (1, 198) <.0001

Baseline hostility—friendly VAMS 8.11 (1, 255) .005 5.62 (1, 201) .019

Baseline anger attack 23.76 (1, 249) <.0001 4.88 (1, 204) .028

Baseline anxious arousal (MASQ‐AA) 0.83 (1, 258) .36 2.02 (1, 207) .16

Baseline depression (HAMD‐17) 0.89 (1, 254) .35 0.08 (1, 201) .77

Baseline CHRT suicide propensity score 0.56 (1, 249) .46 0.07 (1, 198) .38

Baseline self‐reported pain (P‐FIBS) 40.79 (1, 1473) <.0001 19.37 (1, 944) <.0001

Lifetime suicidal tendencies 1.92 (1, 245) .17 0.79 (1, 198) .38

Time 37.59 (6, 1309) <.0001 6.19 (5, 803) <.0001

Time × baseline anger attack interaction 3.11 (6, 1308) .005 1.74 (5, 805) .12

Note: Results of separate mixed model analyses for Stages 1 and 2 of EMBARC study with suicidal ideation (three‐item suicidal thoughts factor of Concise
Health Risk Tracking scale) as the dependent variable, and age, sex, race, ethnicity, site, age, and treatment arm as covariates.
Abbreviations: CAST‐IRR, irritability domain of Concise Associated Symptom Tracking Scale; EMBARC, Establishing Moderators and Biosignatures of
Antidepressant Response in Clinical Care; HAMD‐17, 17‐item Hamilton Depression Rating Scale; MASQ‐AA, Mood and Anxiety Symptom Questionnaire
anxious arousal factor; P‐FIBS, Pain Frequency Intensity and Burden Scale; VAMS, Visual Analogue of Mood Scale.
JHA ET AL.
with fivefold greater likelihood of reporting SI (categorized as score
≥2 on suicide‐related item of the 9‐item Patient Health Ques-
tionnaire) (Start et al., 2019). Remarkably, associations of anger with
these measures of suicidality were significant, even after controlling
for the presence of psychiatric illnesses and severity of depressive
symptoms in both these studies (Hogstedt et al., 2018; Start et al.,
2019). However, to our knowledge, no previous report has identified
an association between anger attacks and SI in patients with MDD
within the context of acute‐phase antidepressant treatment. Fur-
thermore, this report demonstrated that related constructs of anger
attacks and irritability are independently associated with elevated SI.
While anxious arousal and hostility were associated with SI in uni-
variate analyses, their association was no longer significant in mul-
tivariate analyses that controlled for levels of irritability and
presence of anger attacks.
Findings of this report may have direct clinical implications.
Screening for anger attacks in depressed patients may identify those
at risk of persistently elevated SI. Thus, these findings further argue
for systematic assessment of anger attacks and its related constructs
in clinical practice (Jha, Grannemann, et al., 2019; Jha, Minhajuddin,
et al., 2019; Trivedi et al., 2019). While patients with anger attacks
typically experience improvement with antidepressants, previous
reports have found new‐onset anger attacks in a small minority of
patients (Fava et al., 1993, 1997). This is consistent with reports of
worsening irritability and anxiety after antidepressant initiation in
outpatients with MDD (Jha et al., 2018). Thus, there is an urgent
need to develop treatment strategies that specifically target anger
attacks.
4.1 | Limitations
There are several limitations to this report. As EMBARC was not
conducted to test the association between anger attacks and SI, the
study was not adequately powered to further characterize what role,
if any, frequency of anger attacks (number of attacks in the past
month) has on post‐baseline levels of SI. Findings of this report are
based on unplanned secondary analyses. Thus, they should be con-
sidered preliminary and further validation is necessary. Additionally,
because anger attacks were not assessed after the baseline visit, it is
likely that some participants no longer met the criteria for anger
attacks after the end of Stage 1. Thus, this study cannot address
whether remission of anger attacks may have led to reduced SI.
Finally, the EMBARC study was conducted at academic medical
centers and included a comprehensive set of inclusion and exclusion
criteria, which likely restricted the generalizability of these findings
(Zimmerman et al., 2019).
In conclusion, this is the first report, to our knowledge, to de-
monstrate that presence of overt behaviors of anger attacks in pa-
tients with MDD is associated with higher levels of SI before
treatment initiation. Additionally, the higher levels of SI persist even
after 16 weeks of antidepressant treatment suggesting the need for
novel therapeutic developments for this vulnerable group of patients.
| 7
ACKNOWLEDGM E NTS
The authors thank the trial participants and the clinical staff at each
clinical site. Without them, the project would not have been possible.
The authors also thank Georganna Carlock for administrative sup-
port. The EMBARC study was supported by NIMH grants
U01MH092221 (to Dr. Trivedi) and U01MH092250 (to Drs.
McGrath, Parsey, and Weissman). This study was also funded in part
by the Hersh Foundation (Dr. Trivedi, principal investigator). The
content of this publication does not necessarily reflect the views or
policies of the U.S. Department of Health and Human Services, nor
does mention of trade names, commercial products, or organizations
imply endorsement by the U.S. government. NIMH had no role in the
drafting or review of the manuscript or in the collection or analysis of
the data.
CO N FLI CT O F I N TER E S TS
Drs. Minhajuddin and Chin Fatt have no conflicts to report. Dr. Jha
has received contract research grants from Acadia Pharmaceuticals
and Janssen Research & Development, and honoraria for CME pre-
sentations from North American Center for Continuing Medical
Education and Global Medical Education. Dr. Fava has received
research support from Abbot Laboratories Alkermes, American
Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir Pharma-
ceuticals, BioResearch, BrainCells, Bristol‐Myers Squibb, CeNeRx
BioPharma, Cephalon, Clintara, Cerecor, Covance, Covidien, Eli Lilly,
EnVivo Pharmaceuticals, Euthymics Bioscience, Forest Pharmaceu-
ticals, Ganeden Biotech, GlaxoSmithKline, Harvard Clinical Research
Institute, Hoffman‐LaRoche, Icon Clinical Research, i3 Innovus/In-
genix, Janssen R&D, Jed Foundation, Johnson & Johnson Pharma-
ceutical Research and Development, Lichtwer Pharma GmbH, Lorex
Pharmaceuticals, Lundbeck, MedAvante, Methylation Sciences,
NARSAD, National Center for Complementary and Alternative
Medicine, Neuralstem, NIDA, NIMH, Novartis, Organon Pharma-
ceuticals, Pamlab, Pfizer, Pharmacia‐Upjohn, Pharmaceutical
Research Associates, Pharmavite, PharmoRx Therapeutics, Photo-
thera, Reckitt Benckiser, Roche Pharmaceuticals, RCT Logic (for-
merly Clinical Trials Solutions), Sanofi‐Aventis US, Shire, Solvay
Pharmaceuticals, Stanley Medical Research Institute, Synthelabo, Tal
Medical, and Wyeth‐Ayerst Laboratories; he has served as adviser or
consultant to Abbott Laboratories, Acadia, Affectis Pharmaceuticals,
Alkermes, Amarin Pharma, Aspect Medical Systems, AstraZeneca,
Auspex Pharmaceuticals, Avanir Pharmaceuticals, AXSOME
Therapeutics, Bayer, Best Practice Project Management, Biogen,
BioMarin Pharmaceuticals, Biovail Corporation, BrainCells, Bristol‐
Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, CNS
Response, Compellis Pharmaceuticals, Cypress Pharmaceutical, Di-
agnoSearch Life Sciences, Dainippon Sumitomo Pharma, Dov
Pharmaceuticals, Edgemont Pharmaceuticals, Eisai, Eli Lilly, EnVivo
Pharmaceuticals, ePharmaSolutions, EPIX Pharmaceuticals, Eu-
thymics Bioscience, Fabre‐Kramer Pharmaceuticals, Forest Pharma-
ceuticals, Forum Pharmaceuticals, GenOmind, GlaxoSmithKline,
Grunenthal GmbH, i3 Innovus/Ingenis, Intracellular, Janssen Phar-
maceutica, Jazz Pharmaceuticals, Johnson & Johnson Pharmaceutical
8 |
Research and Development, Knoll Pharmaceuticals, Labopharm,
Lorex Pharmaceuticals, Lundbeck, MedAvante, Merck, MSI Methy-
lation Sciences, Naurex, Nestle Health Sciences, Neuralstem, Neu-
ronetics, NextWave Pharmaceuticals, Novartis, Nutrition 21,
Orexigen Therapeutics, Organon Pharmaceuticals, Osmotica, Otsuka
Pharmaceuticals, Pamlab, Pfizer, PharmaStar, Pharmavite, PharmoRx
Therapeutics, Precision Human Biolaboratory, Prexa Pharmaceu-
ticals, Puretech Ventures, PsychoGenics, Psylin Neurosciences, RCT
Logic (Formerly Clinical Trials Solutions), Rexahn Pharmaceuticals,
Ridge Diagnostics, Roche, Sanofi‐Aventis US, Sepracor, Servier La-
boratories, Schering‐Plough, Solvay Pharmaceuticals, Somaxon
Pharmaceuticals, Somerset Pharmaceuticals, Sunovion Pharmaceu-
ticals, Supernus Pharmaceuticals, Synthelabo, Taisho Pharmaceutical,
Takeda Pharmaceutical Company, Tal Medical, Tetragenex Pharma-
ceuticals, TransForm Pharmaceuticals, Transcept Pharmaceuticals,
Vanda Pharmaceuticals, and VistaGen; he has received speaking or
publishing fees from Adamed, Advanced Meeting Partners, American
Psychiatric Association, American Society of Clinical Psycho-
pharmacology, AstraZeneca, Belvoir Media Group, Boehringer In-
gelheim GmbH, Bristol‐Myers Squibb, Cephalon, CME Institute/
Physicians Postgraduate Press, Eli Lilly, Forest Pharmaceuticals,
GlaxoSmithKline, Imedex, MGH Psychiatry Academy/Primedia, MGH
Psychiatry Academy/Reed Elsevier, Novartis, Organon Pharmaceu-
ticals, Pfizer, PharmaStar, United BioSource, and Wyeth‐Ayerst
Laboratories; he has equity holdings in Compellis and PsyBrain; he
has a patent for Sequential Parallel Comparison Design, which are
licensed by Massachusetts General Hospital to Pharmaceutical
Product Development, and a patent application for a combination of
ketamine plus scopolamine in major depressive disorder, licensed by
Massachusetts General Hospital to Biohaven; and he receives roy-
alties for the MGH Cognitive and Physical Functioning Ques-
tionnaire, the Sexual Functioning Inventory, the Antidepressant
Treatment Response Questionnaire, Discontinuation‐Emergent Signs
and Symptoms, the Symptoms of Depression Questionnaire, and
SAFER, and from Lippincott, Williams & Wilkins, Wolkers Kluwer,
and World Scientific Publishing. Dr. Mischoulon has received re-
search support from Nordic Naturals. He has provided unpaid con-
sulting for Pharmavite LLC and Gnosis USA, Inc. He has received
honoraria for speaking from the Massachusetts General Hospital
Psychiatry Academy, Blackmores, Harvard Blog, and PeerPoint
Medical Education Institute, LLC. He has received royalties from
Lippincott Williams & Wilkins for published book “Natural Medica-
tions for Psychiatric Disorders: Considering the Alternatives.” Dr.
Cusin has received research support from Shenox. She has received
consulting honoraria from Janssen, Takeda, Boehringer, Lundbeck,
Alkermes. She has received royalties from Springer for published
book “The Massachusetts General Hospital Guide to Depression.” Dr.
Trivedi has served as an adviser or consultant for Abbott Labora-
tories, Abdi Ibrahim, Akzo (Organon Pharmaceuticals), Alkermes,
AstraZeneca, Axon Advisors, Bristol‐Myers Squibb, Cephalon, Cere-
cor, CME Institute of Physicians, Concert Pharmaceuticals, Eli Lilly,
Evotec, Fabre Kramer Pharmaceuticals, Forest Pharmaceuticals,
GlaxoSmithKline, Janssen Global Services, Janssen Pharmaceutica
JHA ET AL.
Products, Johnson & Johnson PRD, Libby, Lundbeck, Meade Johnson,
MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Devel-
opment America, Naurex, Neuronetics, Otsuka Pharmaceuticals,
Pamlab, Parke‐Davis Pharmaceuticals, Pfizer, PgxHealth, Phoenix
Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics,
Roche Products, Sepracor, Shire Development, Sierra, SK Life and
Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targa-
cept, Transcept, VantagePoint, Vivus, and Wyeth‐Ayerst Labora-
tories; he has received grants or research support from the Agency
for Healthcare Research and Quality, Cyberonics, NARSAD, NIDA,
and NIMH.
DATA A VAILABILITY STA TEMENT
Data for EMBARC study are publicly available through the National
Institute of Mental Health Data Archive at https://nda.nih.gov/edit_
collection.html?id=2199.
OR C ID
Madhukar H. Trivedi http://orcid.org/0000-0002-2983-1110
REFER E NC ES
Beck, A. T., Steer, R. A., Beck, J. S., & Newman, C. F. (1993). Hopelessness,
depression, suicidal ideation, and clinical diagnosis of depression.
Suicide & Life‐Threatening Behavior, 23(2), 139–145.
Chandler, G. M., Iosifescu, D. V., Pollack, M. H., Targum, S. D., & Fava, M.
(2010). RESEARCH: Validation of the Massachusetts General
Hospital Antidepressant Treatment History Questionnaire (ATRQ).
CNS Neuroscience & Therapeutics, 16(5), 322–325. https://doi.org/10.
1111/j.1755-5949.2009.00102.x
Conner, K. R., Meldrum, S., Wieczorek, W. F., Duberstein, P. R., &
Welte, J. W. (2004). The association of irritability and impulsivity
with suicidal ideation among 15‐ to 20‐year‐old males. Suicide and
Life‐Threatening Behavior, 34(4), 363–373. https://doi.org/10.1521/
suli.34.4.363.53745
Curtin, S., & Hedegaard, H. (2019). Suicide rates for females and males
by race and ethnicity: United States, 1999 and 2017. NCHS Health
E‐Stat. https://www.cdc.gov/nchs/data/hestat/suicide/rates_1999_
2017.pdf
dela Cruz, A. M., Bernstein, I. H., Greer, T. L., Walker, R., Rethorst, C. D.,
Grannemann, B., Carmody, T., & Trivedi, M. H. (2014). Self‐rated
measure of pain frequency, intensity, and burden: Psychometric
properties of a new instrument for the assessment of pain. Journal of
Psychiatric Research, 59, 155–160. https://doi.org/10.1016/j.jpsychires.
2014.08.003
Ducasse, D., Jaussent, I., Guillaume, S., Azorin, J. M., Bellivier, F., Belzeaux, R.,
Bougerol, T., Etain, B., Gard, S., Henry, C., Kahn, J. P., Leboyer, M.,
Loftus, J., Passerieux, C., FondaMental Advanced Centers of
Expertise in Bipolar Disorders (FACE‐BD) Collaborators, Olié, E., &
Courtet, P. (2017). Affect lability predicts occurrence of suicidal ideation
in bipolar patients: A two‐year prospective study. Acta Psychiatrica
Scandinavica, 135(5), 460–469. https://doi.org/10.1111/acps.12710
Fanning, J. R., Lee, R., & Coccaro, E. F. (2016). Comorbid intermittent
explosive disorder and posttraumatic stress disorder: Clinical
correlates and relationship to suicidal behavior. Comprehensive
Psychiatry, 70, 125–133. https://doi.org/10.1016/j.comppsych.
2016.05.018
Fava, M., Anderson, K., & Rosenbaum, J. F. (1990). "Anger attacks":
Possible variants of panic and major depressive disorders. American
Journal of Psychiatry, 147(7), 867–870. https://doi.org/10.1176/ajp.
147.7.867
JHA ET AL.
Fava, M., Nierenberg, A. A., Quitkin, F. M., Zisook, S., Pearlstein, T.,
Stone, A., & Rosenbaum, J. F. (1997). A preliminary study on the
efficacy of sertraline and imipramine on anger attacks in atypical
depression and dysthymia. Psychopharmacology Bulletin, 33(1),
101–103.
Fava, M., Rosenbaum, J. F., Pava, J. A., McCarthy, M. K., Steingard, R. J., &
Bouffides, E. (1993). Anger attacks in unipolar depression, Part 1:
Clinical correlates and response to fluoxetine treatment. American
Journal of Psychiatry, 150(8), 1158–1163. https://doi.org/10.1176/
ajp.150.8.1158
Fishbain, D. A., Lewis, J. E., & Gao, J. (2014). The pain suicidality
association: A narrative review. Pain Medicine, 15(11), 1835–1849.
https://doi.org/10.1111/pme.12463
Hamilton, M. (1960). A rating scale for depression. Journal of Neurology,
Neurosurgery and Psychiatry, 23, 56–62. https://doi.org/10.1136/
jnnp.23.1.56
Hogstedt, C., Forsell, Y., Hemmingsson, T., Lundberg, I., & Lundin, A.
(2018). Psychological symptoms in late adolescence and long‐term
risk of suicide and suicide attempt. Suicide & Life‐Threatening
Behavior, 48(3), 315–327. https://doi.org/10.1111/sltb.12362
Jang, J. M., Park, J. I., Oh, K. Y., Lee, K. H., Kim, M. S., Yoon, M. S., Ko, S. H.,
Cho, H. C., & Chung, Y. C. (2014). Predictors of suicidal ideation in a
community sample: Roles of anger, self‐esteem, and depression.
Psychiatry Research, 216(1), 74–81. https://doi.org/10.1016/j.
psychres.2013.12.054
Jha, M. K., Fava, M., Minhajuddin, A., Fatt, C. C., Mischoulon, D.,
Wakhlu, N., Trombello, J. M., Cusin, C., & Trivedi, M. H. (2020).
Anger attacks are associated with persistently elevated irritability in
MDD: Findings from the EMBARCstudy. Psychological Medicine, 1–9.
https://doi.org/10.1017/S0033291720000112
Jha, M. K., Grannemann, B. D., Trombello, J. M., Clark, E. W.,
Eidelman, S. L., Lawson, T., Greer, T. L., Rush, A. J., & Trivedi, M. H.
(2019). A structured approach to detecting and treating depression
in primary care: VitalSign6 project. Annals of Family Medicine, 17(4),
326–335. https://doi.org/10.1370/afm.2418
Jha, M. K., Minhajuddin, A., Fatt, C. C., Kircanski, K., Stringaris, A.,
Leibenluft, E., & Trivedi, M. (2020). Association between irritability
and suicidal ideation in three clinical trials of adults with major
depressive disorder. Neuropsychopharmacology, https://doi.org/10.
1038/s41386-020-0769-x
Jha, M. K., Minhajuddin, A., South, C., Rush, A. J., & Trivedi, M. H. (2018).
Worsening Anxiety, irritability, insomnia, or panic predicts poorer
antidepressant treatment outcomes: Clinical Utility and Validation
of the Concise Associated Symptom Tracking (CAST) scale.
International Journal of Neuropsychopharmacology, 21(4), 325–332.
https://doi.org/10.1093/ijnp/pyx097
Jha, M. K., Minhajuddin, A., South, C., Rush, A. J., & Trivedi, M. H. (2019).
Irritability and its clinical utility in major depressive disorder:
Prediction of individual‐level acute‐phase outcomes using early
changes in irritability and depression severity. American Journal of
Psychiatry, 176(5), 358–366. https://doi.org/10.1176/appi.ajp.2018.
18030355
Kampfer, N., Staufenbiel, S., Wegener, I., Rambau, S., Urbach, A. S.,
Mucke, M., Geiser, F., & Conrad, R. (2016). Suicidality in patients with
somatoform disorder—The speechless expression of anger? Psychiatry
Research, 246, 485–491. https://doi.org/10.1016/j.psychres.2016.
10.022
Mayes, T. L., Killian, M., Rush, A. J., Emslie, G. J., Carmody, T., Kennard, B. D.,
Jha, M. K., King, J., Hughes, J. L., & Trivedi, M. H. (2020). Predicting
future suicidal events in adolescents using the Concise Health Risk
Tracking Self‐Report (CHRT‐SR). Journal of Psychiatric Research, 126,
19–25. https://doi.org/10.1016/j.jpsychires.2020.04.008
McCloskey, M. S., & Ammerman, B. A. (2018). Suicidal behavior and
aggression‐related disorders. Current Opinion in Psychology, 22,
54–58. https://doi.org/10.1016/j.copsyc.2017.08.010
| 9
Oquendo, M. A., Currier, D., & Mann, J. J. (2006). Prospective studies of
suicidal behavior in major depressive and bipolar disorders: What is
the evidence for predictive risk factors? Acta Psychiatrica
Scandinavica, 114(3), 151–158. https://doi.org/10.1111/j.1600-
0447.2006.00829.x
Orri, M., Galera, C., Turecki, G., Boivin, M., Tremblay, R. E., Geoffroy,
M.‐C., & Côté, S. M. (2019). Pathways of Association Between
Childhood Irritability and Adolescent Suicidality. Journal of the
American Academy of Child & Adolescent Psychiatry, 58(1), 99–107.
https://doi.org/10.1016/j.jaac.2018.06.034
Orri, M., Galera, C., Turecki, G., Forte, A., Renaud, J., Boivin, M.,
Tremblay, R. E., Côté, S. M., & Geoffroy, M.‐C. (2018). Association of
childhood irritability and depressive/anxious mood profiles with
adolescent suicidal ideation and attempts. JAMA Psychiatry, 75(5),
465–473. https://doi.org/10.1001/jamapsychiatry.2018.0174
Orri, M., Perret, L. C., Turecki, G., & Geoffroy, M. C. (2018). Association
between irritability and suicide‐related outcomes across the life‐
course. Systematic review of both community and clinical studies.
Journal of Affective Disorders, 239, 220–233. https://doi.org/10.
1016/j.jad.2018.07.010
Pickles, A., Aglan, A., Collishaw, S., Messer, J., Rutter, M., & Maughan, B.
(2009). Predictors of suicidality across the life span: The Isle of
Wight study. Psychological Medicine, 40(9), 1453–1466. https://doi.
org/10.1017/S0033291709991905
Pizzagalli, D. A., Evins, A. E., Schetter, E. C., Frank, M. J., Pajtas, P. E.,
Santesso, D. L., & Culhane, M. (2008). Single dose of a dopamine
agonist impairs reinforcement learning in humans: Behavioral evidence
from a laboratory‐based measure of reward responsiveness.
Psychopharmacology, 196(2), 221–232. https://doi.org/10.1007/s002
13-007-0957-y
Racine, M., Sanchez‐Rodriguez, E., Galan, S., Tome‐Pires, C., Sole, E.,
Jensen, M. P., Nielson, W. R., Miró, J., Moulin, D. E., & Choiniere, M.
(2017). Factors associated with suicidal ideation in patients with
chronic non‐cancer pain. Pain Medicine, 18(2), 283–293. https://doi.
org/10.1093/pm/pnw115
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B.,
Klein, D. N., Markowitz, J. C., Ninan, P. T., Kornstein, S., Manber, R.,
Thase, M. E., Kocsis, J. H, & Keller, M. B (2003). The 16‐Item Quick
Inventory of Depressive Symptomatology (QIDS), clinician rating
(QIDS‐C), and self‐report (QIDS‐SR): A psychometric evaluation in
patients with chronic major depression. Biological Psychiatry, 54(5),
573–583. https://doi.org/10.1016/s0006-3223(02)01866-8
Start, A. R., Allard, Y., Adler, A., & Toblin, R. (2019). Predicting suicide
ideation in the military: The independent role of aggression. Suicide &
Life‐Threatening Behavior, 49(2), 444–454. https://doi.org/10.1111/
sltb.12445
Steelesmith, D. L., Fontanella, C. A., Campo, J. V., Bridge, J. A.,
Warren, K. L., & Root, E. D. (2019). Contextual factors associated
with county‐level suicide rates in the United States, 1999 to 2016.
JAMA Netw Open, 2(9), e1910936. https://doi.org/10.1001/
jamanetworkopen.2019.10936
Stringer, B., van Meijel, B., Eikelenboom, M., Koekkoek, B., Licht, C. M. M.,
Kerkhof, A. J. F. M., Penninx, B. W. J. H., & Beekman, A. T. F. (2013).
Recurrent suicide attempts in patients with depressive and anxiety
disorders: The role of borderline personality traits. Journal of
Affective Disorders, 151(1), 23–30. https://doi.org/10.1016/j.jad.
2013.02.038
Trivedi, M. H., Jha, M. K., Kahalnik, F., Pipes, R., Levinson, S., Lawson, T.,
Rush, A. J., Trombello, J. M., Grannemann, B., Tovian, C., Kinney, R.,
Clark, E. W., & Greer, T. L. (2019). VitalSign(6): A Primary Care First
(PCP‐First) model for universal screening and measurement‐based
care for depression. Pharmaceuticals, 12(2), 71. https://doi.org/10.
3390/ph12020071
Trivedi, M. H., McGrath, P. J., Fava, M., Parsey, R. V., Kurian, B. T.,
Phillips, M. L., Oquendo, M. A., Bruder, G., Pizzagalli, D., Toups, M.,
10 | JHA
Cooper, C., Adams, P., Weyandt, S., Morris, D. W,
Grannemann, M. M, Ogden, R. T, Buckner, R., McInnis, M.,
Kraemer, H. C., … Weissman, M. M. (2016). Establishing moderators
and biosignatures of antidepressant response in clinical care
(EMBARC): Rationale and design. Journal of Psychiatric Research, 78,
11–23. https://doi.org/10.1016/j.jpsychires.2016.03.001
Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D.,
Ritz, L., Norquist, G., Howland, R. H., Lebowitz, B., McGrath, P. J.,
Shores‐Wilson, K., Biggs, M. M., Balasubramani, G. K., Fava, M., &
STAR*D Study Team. (2006). Evaluation of outcomes with
citalopram for depression using measurement‐based care in
STAR*D: implications for clinical practice. American Journal of
Psychiatry, 163(1), 28–40. https://doi.org/10.1176/appi.ajp.163.1.28
Trivedi, M. H., South, C., Jha, M. K., Rush, A. J., Cao, J., Kurian, B.,
Phillips, M., Pizzagalli, D. A., Trombello, J. M., Oquendo, M. A.,
Cooper, C., Dillon, D. G., Webb, C., Grannemann, B. D., Bruder, G.,
McGrath, P. J., Parsey, R., Weissman, M., & Fava, M. (2018). A novel
strategy to identify placebo responders: Prediction index of clinical
and biological markers in the EMBARC trial. Psychotherapy and
Psychosomatics, 87(5), 285–295. https://doi.org/10.1159/000491093
Trivedi, M. H., Wisniewski, S. R., Morris, D. W., Fava, M., Kurian, B. T.,
Gollan, J. K., Nierenberg, A. A., Warden, D., Gaynes, B. N.,
Luther, J. F., & Rush, A. J. (2011). Concise Associated Symptoms
Tracking scale: A brief self‐report and clinician rating of symptoms
associated with suicidality. Journal of Clinical Psychiatry, 72(6),
765–774. https://doi.org/10.4088/JCP.11m06840
Trombello, J. M., Killian, M. O., Grannemann, B. D., Rush, A. J., Mayes, T. L.,
Parsey, R. V., McInnis, M., Jha, M.K., Ali, A., McGrath, P. J., Adams, P.,
Oquendo, M. A., Weissman, M. M., Carmody, T. J., & Trivedi, M. H.
(2019). The Concise Health Risk Tracking‐Self Report:
Psychometrics within a placebo‐controlled antidepressant trial
among depressed outpatients. Journal of Psychopharmacology, 33(2),
185–193. https://doi.org/10.1177/0269881118817156
Wardenaar, K. J., van Veen, T., Giltay, E. J., de Beurs, E., Penninx, B. W., &
Zitman, F. G. (2010). Development and validation of a 30‐item short
ET AL.
adaptation of the Mood and Anxiety Symptoms Questionnaire
(MASQ). Psychiatry Research, 179(1), 101–106. https://doi.org/10.
1016/j.psychres.2009.03.005
Wilks, C. R., Morland, L. A., Dillon, K. H., Mackintosh, M. A.,
Blakey, S. M., Wagner, H. R., & Elbogen, E. B. (2019). Anger, social
support, and suicide risk in U.S. military veterans. Journal of
Psychiatric Research, 109, 139–144. https://doi.org/10.1016/j.
jpsychires.2018.11.026
Zhang, W., Ding, H., Su, P., Xu, Q., Du, L., Xie, C., Chen, R., Yang, Y., Jin, C.,
Duan, G., Li, Y., Gong, L., & Tian, W. (2017). Prevalence and risk
factors for attempted suicide in the elderly: A cross‐sectional study
in Shanghai, China. International Psychogeriatrics, 29(5), 709–715.
https://doi.org/10.1017/s1041610216002283
Zimmerman, M., Balling, C., Chelminski, I., & Dalrymple, K. (2019). Have
treatment studies of depression become even less generalizable?
Applying the inclusion and exclusion criteria in placebo‐controlled
antidepressant efficacy trials published over 20 years to a clinical
sample. Psychotherapy and Psychosomatics, 88(3), 165–170. https://
doi.org/10.1159/000499917
SU PP O RT I N G I N FO RM ATI ON
Additional Supporting Information may be found online in the
supporting information tab for this article.
How to cite this article: Jha MK, Fava M, Minhajuddin A,
et al. Association of anger attacks with suicidal ideation in
adults with major depressive disorder: Findings from the
EMBARC study. Depress Anxiety. 2020;1–10.
https://doi.org/10.1002/da.23095