Academic Highlights

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This A H
cademicsection of The Journal of Clinical
ighlights
Psychiatry presents the highlights of the videoconference
Utilizing the DSM-5 Anxious
“Utilizing the Anxious Distress Specifier to Develop
Treatment Strategies for Patients With Major Depressive
Distress Specifier to Develop
Disorder,” which was held in June 2017.
The videoconference was chaired by Michael E. Thase,
Treatment Strategies for Patients
With Major Depressive Disorder

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MD, Director, Mood and Anxiety Program, and Professor
of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania. The faculty were Richard H. Weisler, MD,

M
Adjunct Professor of Psychiatry, University of North Carolina
at Chapel Hill; J. Sloan Manning, MD, Adjunct Associate any patients with depression also experience anxiety
Professor, Department of Family Medicine at the University symptoms. For some, these symptoms reflect a coexisting,
of North Carolina, Chapel Hill; and Madhukar H. Trivedi, ongoing anxiety disorder, while for others, a significant surge in
MD, Professor of Psychiatry, University of Texas Southwestern
anxiety occurs along with—and complicates the clinical picture of—
Medical Center, Dallas, Texas.
depressive episodes. The importance of anxious features that occur
Financial disclosures: Dr Thase has been an advisor/
consultant for Acadia, Alkermes, Allergan (Forest, Naurex), in the context of depressive episodes has been recognized in DSM-5
AstraZeneca, Cerecor, Eli Lilly, Fabre-Kramer, Gerson Lehrman with the addition of an anxious distress specifier.
Group, Guidepoint Global, Johnson & Johnson, (Janssen, In this Academic Highlights, psychiatrists Michael E. Thase,
Ortho-McNeil), Lundbeck, MedAvante, Merck, Moksha8, MD; Richard H. Weisler, MD; and Madhukar H. Trivedi, MD,
Nestlé (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion,
and Takeda; has received grant support from Agency for and primary care physician J. Sloan Manning, MD, engage in a
Healthcare Research and Quality, Alkermes, AssureRx, discussion on the prevalence of anxiety in depressed patients, the
Avanir, Forest, Janssen, Intracellular, National Institute of emergence of the DSM-5 anxious distress specifier, characteristics
Mental Health, Otsuka, and Takeda; has equity holdings associated with this symptom profile, and screening and treatment
in MedAvante; and has received royalties from American
Psychiatric Foundation, Guilford Publications, Herald House, strategies.
and W. W. Norton & Company. Dr Thase’s spouse is employed
by Peloton Advantage. Dr Manning has been a consultant
for and served on speakers/advisory boards for Otsuka, PREVALENCE OF ANXIOUS SYMPTOMS IN MDD
Takeda, Lundbeck, Alkermes, and Sunovion. Dr Weisler has
been a consultant to Alcobra, AltheaDx, lronshore, Lundbeck, Dr Thase began the discussion by stating that the prevalence
Major League Baseball (certified MLB clinician [therapeutic of anxiety symptoms in MDD patients is between 40% and 60%.
use exemption]), National Football League (certified NFL Gaspersz et al,1 in the Netherlands Study of Depression and Anxiety
clinician [therapeutic use exemption]), Neos Therapeutics,
(NESDA), identified items on various self-report measures that
Nestlé Health Science-PamLab, Otsuka America, Rhodes,
Shire, Sunovion, Supernus, and Validus; served on the corresponded to DSM-5 anxious distress specifier criteria and found
speakers bureaus of Lundbeck, Neos Therapeutics, Nestlé a prevalence of 54%. In a large sample of psychiatric outpatients with
Health Science-PamLab, Otsuka America, Rhodes, Shire, MDD, Zimmerman et al2 demonstrated an even higher prevalence of
Sunovion, and Validus; and received research support from
Alcobra, Allergan, Daiichi Sankyo, Genomind, Janssen, Merck,
patients who met specifier criteria, 78%. Further, the prevalence has
Neurim, Otsuka America, Roche-Genentech, Shire, Suven Life been shown to be higher in primary care than in specialty care.3
Sciences, and Theravance. Dr Trivedi has been a consultant
to Alkermes, Allergan, Acadia, AstraZeneca, Bristol-Myers
Squibb, Cerecor, Global Medical Education, Health Research DSM-5 ANXIOUS DISTRESS SPECIFIER
Assoc, Lundbeck, Medscape, MSI Methylation Services,
Merck, Naurex, Nestlé Health Science-PamLab, One Carbon The DSM-5 “with anxious distress” specifier4(p184) can be
Therapeutics, Otsuka America, PamLab, Pfizer, Roche, Shire appended to depressive diagnoses and allows clinicians to both note
Development, and Takeda; received grant/research support the presence and rate the severity of anxiety symptoms. The specifier
from National Institute of Mental Health, National Institute
on Drug Abuse, Johnson & Johnson, and Janssen R&D; and may be used for patients with at least 2 of the following symptoms
received other financial/material support from Janssen R&D. during the majority of days of a major depressive episode:
This evidence-based peer-reviewed Academic Highlights was • Feeling keyed up or tense
prepared by Healthcare Global Village, Inc. Financial support • Feeling unusually restless
for preparation and dissemination of this Academic Highlights
was provided by Otsuka Pharmaceutical Development & • Difficulty concentrating due to worry
Commercialization, Inc., and Lundbeck, Inc. The faculty • Fear that something awful may happen
acknowledges Sarah Brownd, MA, for editorial assistance in • Feeling loss of control of himself or herself
developing the manuscript. The opinions expressed herein
are those of the faculty and do not necessarily reflect the Clinicians can gauge severity on the basis of the number of
views of Healthcare Global Village, Inc, the publisher, or the symptoms displayed:
commercial supporters. This article is distributed by Otsuka
Pharmaceutical Development & Commercialization, Inc., and 0 or 1 symptom = no anxious distress,
Lundbeck, Inc., for educational purposes only. 2 symptoms = mild anxious distress,
J Clin Psychiatry 2017;78(9):1351–1362 3 symptoms = moderate anxious distress, and
https://doi.org/10.4088/JCP.ot17015ah1 4–5 symptoms = moderate to severe anxious distress
© Copyright 2017 Physicians Postgraduate Press, Inc. (psychomotor agitation must be present).

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1351   J Clin Psychiatry 78:9, November/December 2017
 Academic Highlights

ItInis
theirillegal to post
overview of DSM-5 this
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that severity-based specifiers may be particularly informative ■■ Between 40% and 60% of patients with major depressive
disorder (MDD) also have anxiety symptoms. An anxious
because treatment for mild symptoms should differ from
distress specifier was included in DSM-5 to help identify
treatment for moderate-to-severe presentations. The specifier and treat patients with this symptom profile.
includes symptoms that, although they are not a part of the
criteria for most mood disorders (eg, difficulty concentrating
■■ Anxious distress in MDD is associated with greater

Clinical Points
depression severity and poorer response to treatment, as
because of worry), may describe a disorder variant that well as lower functioning and increased suicidality.
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causes distress and merits attention in treatment choice. Part ■■ Objectively measuring symptoms at each visit helps
of the DSM-5 task force’s reasoning for the addition was to clinicians diagnose more precisely and make better-
allow clinicians to assign a specifier that yields information informed treatment choices. Several brief, easy-to-
for treatment planning and tracking efforts that might have administer scales are available for this purpose.
been previously obscured under a residual diagnosis of “not ■■ SSRIs and psychotherapy are first-line treatment options.
otherwise specified” in DSM-IV.5 “Mixed anxiety-depressive If these yield inadequate response after a sufficient
disorder” was included in DSM-IV as an area for further length of time, switching antidepressants or combining
research, but not as an official diagnosis. Anxious depression treatment modalities, such as augmenting with atypical
antipsychotics, should be considered.
has been defined dimensionally, syndromally, and as mixed-
anxiety depressive disorder (depression and anxiety that do not
meet criteria for either disorder).6 The specifier reflects a shift
toward a dimensional, severity-based approach. Because such a large proportion of patients meet specifier
criteria, Dr Manning thought that denoting the absence of
Previous Ways of Recognizing Anxious Distress anxious distress might have been more appropriate, or that the
The term anxious depression has long been used to DSM-5 requirement of meeting 2 of 5 criteria for the majority
describe the emergence of anxiety in the setting of a of the depressive episode could be raised to 3 of 5 criteria to
depressive episode, and synthesis of research findings has more clearly differentiate severe distress. Along these lines, Dr
been complicated by heterogeneous definitions of anxious Trivedi noted that the number of anxious symptoms exhibited
depression. Diagnosis in research settings has typically been by the patient is significant—those with 3 or 4 symptoms may
based on a DSM or ICD diagnosis of MDD presenting with be at greater risk and have poorer outcomes than those with
subthreshold anxiety symptoms measured using a variety of 1 or 2. He speculated that although the specifier’s minimum
tools and score cutoffs,6 such as the Hamilton Depression cutoff of 2 symptoms might not have been derived from hard
Rating Scale (HDRS) anxiety/somatization factor (score ≥ 7), data, it had most likely been chosen because it made good
the Hamilton Anxiety Rating Scale (HARS) total score, or sense to the experts formulating the criteria.
a mix of items from scales such as the Montgomery-Asberg
Depression Rating Scale (MADRS) and the Inventory for
Depressive Symptomatology.7 Dr Manning said that he
PRESENTATION OF MDD WITH
does not perceive a meaningful difference between previous ANXIOUS DISTRESS
conceptions of “anxious depression” and what is captured Time Course
by the anxious distress specifier—therefore, as was true Anxious symptoms often precede depressive symptoms
previously, best practices in the clinical setting include in patients who develop both, as noted by Drs Trivedi and
effective screening and tracking of anxiety symptoms in Thase. In the WHO World Mental Health Surveys, 68.0%
depressed patients. Dr Thase felt that the specifier represents of those with lifetime anxious MDD reported onset of
a positive change in the nomenclature in that it denotes anxiety disorders at earlier ages than MDD.9 A temporal
patients who tend to have poorer outcomes. The rating scale sequencing analysis10 of NESDA data found that anxious
included within the specifier allows clinicians to codify the symptoms emerged before depressive symptoms in about
extent of the patient’s anxiety as opposed to simply noting the 57% of individuals with both; depressive symptoms were
presence of anxiety. first in only 18% of cases, and in 25% of cases, they emerged
simultaneously. An onset pattern with anxiety first was
Validation associated with longer symptom duration, earlier age at onset
Two validation studies of the anxious distress specifier of the first disorder, and a greater number of fear symptoms.10
have been conducted.1,8 Using data from NESDA, Gaspersz
et al1 showed that the specifier better predicted chronicity, Patient Characteristics
time to remission, and functional disability outcomes in Anxious depression has been shown to be significantly
MDD patients than did DSM-IV anxiety disorder diagnoses.1 more common among women11,12; African Americans
Zimmerman et al8 modified the Clinically Useful Depression and Hispanics13; and those who are married, divorced, or
Outcome Scale to include items keyed to the specifier and widowed versus single.13 Associations with lower education
found their scale to be a reliable and valid predictor of anxiety level,13–15 unemployment,12 and being on public insurance13
symptoms; further, the specifier was associated with greater have also been demonstrated. A NESDA analysis10 found,
functional impairment and poorer quality of life. further, that those with anxious depression had higher

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J Clin Psychiatry 78:9, November/December 2017   1352
Academic Highlights

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Figure 1. Time to Remission in Anxious vs Nonanxious
Figure 2. Psychosocial Functioning in MDD Patients Who Did
Depressiona and Did Not Meet the DSM-5 Anxious Distress Specifiera

Anxious specifier absent (n = 171)

Difficulty Caused by Depression Symptoms

1.0 HR = 0.65 (95% CI, 0.50−0.85), P = .001 3.5
Anxious specifier present (n = 370) *
3 *
0.8 * *
Cumulative Nonresponse

(Modified DID score)

2.5

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0.6 *
Anxious depression 2 *
1.5
0.4
1
0.2
0.5
Nonanxious depression
0.0 0

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aReprinted with permission from Wiethoff et al.15 Figure shows data
from 429 patients in the German Algorithm Project; Cox regression a
Data from Zimmerman et al.8 Scores reflect a modification of the
analysis results are adjusted for baseline severity. Diagnostic Inventory for Depression (DID) on which patients rated how
much difficulty they were having in 6 areas; items were rated from
0 = no difficulty to 4 = extreme difficulty.
*P < .001.
neuroticism scores and lower levels of extraversion, Abbreviation: MDD = major depressive disorder.
agreeableness, and conscientiousness. An association with
childhood trauma was mentioned in the meeting; supporting
that point, Hovens and colleagues showed greater risk
of onset16 and a more chronic course of depression and CONSEQUENCES OF LACK OF DIAGNOSIS
comorbid anxiety/depression17 in those with childhood AND TREATMENT
emotional neglect and psychological abuse. Earlier age at
onset of MDD has also been reported; Fava et al12 found that Effects on the Patient’s Family and Children
the mean age at onset of first major depressive episode for Symptoms of depression and anxiety have consequences not
those with anxious versus nonanxious depression was 24.7 vs just for the affected individual but also for the person’s family.
25.5 years (P = .0064). Drs Thase and Manning found the Sequenced Treatment
Alternatives to Relieve Depression (STAR*D)-Child study,20
Response to Treatment and Remission Rates which looked at the impact of mothers’ unremitted depression
The participants agreed that anxious patients are known on their children, particularly meaningful. Effective treatment
to be more difficult to treat, more severely depressed, and less of women was associated with reduction of symptoms and
responsive to treatment. Depressed patients with anxiety take diagnosis rates in their children in essentially a dose-response
longer to respond to medications—in Dr Thase’s estimation, relationship—and more persistent depression in the mothers
2 to 4 weeks longer. They also have a longer time to remission was linked to development of more psychiatric difficulties in
(Figure 1)15 and are less likely to experience remission.18 their children. Dr Thase commented astutely that people who
Further, anxiety symptoms tend to linger: Romera et al19 might be ambivalent about pursuing treatment for depression
showed that after 3 months of antidepressant treatment, need look no further than the well-being of their children,
78.2% of patients had residual anxiety symptoms. Remission because it is directly dependent on their own well-being.
rates are significantly lower in patients with anxious
depression following initial antidepressant treatment. In a Poorer Prognosis
NESDA-based sample of 149 patients with MDD,14 those Functioning. The participants concurred that in
who met anxious distress specifier criteria were significantly depressed patients, anxiety is a signaler of greater suffering,
less likely to achieve remission after 2 years of adequate mental anguish, and lower functioning. Among psychiatric
antidepressant treatment: 43.2% still had MDD, versus outpatients, Zimmerman et al8 found significantly lower
only 21.3% of those without the specifier. The specifier psychosocial functioning, reduced life satisfaction, and
also predicted more severe depression at both 1-year and poorer quality of life among depressed patients who met the
2-year follow-up. The specifier was better at predicting DSM-5 anxious distress specifier (Figure 2). Worse cognitive
lower remission rates than were comorbid DSM-IV anxiety function and poorer work and social adjustment have also been
disorders. Findings have not been completely uniform, with demonstrated.11 A primary care study21 showed that about 10%
one large study11 showing no difference in time to response of eligible patients screened in clinic waiting rooms reported
at 12 and 28 weeks between MDD patients with and without unrecognized and untreated anxiety symptoms. These patients
anxious features. reported significantly worse functioning on both physical and
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1353   J Clin Psychiatry 78:9, November/December 2017
 Academic Highlights

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emotional measures than nonanxious patients. A striking
CASE VIGNETTE 1 *
finding was that the anxious patients reported reduced
Shari, a 36-year-old woman, presented with psychiatric
functioning within ranges to be expected in chronic physical symptoms that had increased over the past 6 months, beginning
diseases such as diabetes and congestive heart failure. The when her father had a myocardial infarction. Although he
most severe reductions were reported when anxiety was mixed recovered, Shari’s distress did not, and her worries shifted to matters
with depressive disorders. such as her children’s well-being, her husband’s heart attack risk,
Dr Weisler pointed to the cascading effects of poor and the possibility of unlikely events, such as auto accidents.
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functioning. Poorer functioning can lead to dropping out of Shari’s predominant mood was low, but she was often anxious
high school or college, which leads to increased mortality and tense and reported increased musculoskeletal pain. She felt
rates. In fact, mortality attributable to low education is guilty for letting her family down, reported poor concentration,
comparable to that attributable to smoking.22 and could not fall asleep for 1–2 hours each night despite being
tired. Her appetite was decreased except for occasional episodes
Sleep problems. Sleep problems were cited as being
of “nervous” binge eating. She was less interested in spending time
particularly troublesome in anxious depression. For example,
with her friends, and she had diminished enthusiasm for sex. She
Fava et al12 demonstrated substantially higher insomnia rates did not have suicidal ideation but sometimes wondered if she could
in anxious depression (82%, 90%, and 66% for early, middle, go on feeling this way. She also said that the current anxious and
and late insomnia) versus nonanxious depression (60%, 77%, depressive symptoms were unusual for her.
and 47%). Dr Trivedi noted further that there seems to be a
dose-response relationship between anxiety severity and sleep Shari’s symptoms, which had continued for a significant
problems, in that patients who have 3 to 5 of the symptoms period of time, are consistent with a DSM-5 diagnosis of MDD
in the anxious distress specifier seem to have higher rates with anxious distress. Her diminished concentration, low
of sleep disorders than those with 2 or fewer. The National mood, and sleep disturbance all point to an MDD diagnosis;
Comorbidity Survey Replication linked anxiety to comorbid the additional presence of tension and excessive worry and her
persistent feeling that something awful could happen at any
sleep disorders, finding a prevalence of 37% among those with
time further suggest that application of the anxious distress
any anxiety disorder (among those with any mood disorder,
specifier is appropriate.
the prevalence was 25%).23 Sleep complaints in those with
anxious depression are especially troubling because of the link
between sleep problems and suicidality.24
Suicidality. The American Psychiatric Association (APA) SCREENING AND MEASUREMENT
practice guideline for MDD lists severe anxiety as a factor to
Measurement-Based Care
consider when assessing suicide risk and recommends treating
The participants agreed that it is essential that clinicians
it as a modifiable risk factor to lower the risk of suicide in
screen for and track anxiety and depression symptoms,
addition to treating the depressive episode.25 Anxious distress
and the APA recommends measuring outcomes as part of
in those with MDD has been associated with increased
good clinical practice.25 Measurement-based care can be
suicidal ideation13,14 and attempts.13 Dr Weisler mentioned
summarized as systematic and quantitative measurement of
that as the number of anxiety symptoms increases, so does
symptoms at each visit; other parameters such as treatment
suicidality. Impulsivity was also identified by Drs Weisler and
adherence, psychosocial functioning, and side effects should
Thase as a key factor: according to Dr Thase, attempts among
also be assessed.
those with anxious depression “are not the planned suicides;
Measurement-based care is especially important in patients
not the ones in which the person has written a note, but rather
who have depression with co-occurring anxiety symptoms
the ones in which the person shoots themselves or jumps
because, as Dr Manning put it, “People will say, ‘My nerves
off the roof because they can’t stand feeling the way they do
are bad,’ and they typically talk about that in relationship
any longer.” Further, he believes that an intolerance of strong
to anxiety or irritability. That’s one reason we measure with
negative affects plays a part in the development of suicidality
scales: to get discrimination around the symptoms they’re
in these individuals and that the intensity of the anxiety is the
having so that we can make a precise diagnosis and prescribe
“coup de grâce.” Impulsivity makes suicidality in these patients
rational treatment.” He also underscored the importance of
more difficult to predict and prevent.
asking questions about the patient’s own goals for treatment
Increased cardiovascular risk. The American Heart
and approaching the patient empathetically: “There’s the
Association classifies MDD as a tier II moderate-risk
surface analysis, and then there’s the collaborative, empathetic
condition associated with accelerated atherosclerosis and
kind of conversation: ‘So, how can I best help you? What were
early development of cardiovascular disease,26 and a meta-
your hopes for being here today? And I know that everybody
analysis27 showed an overall odds ratio (OR) of 1.60 for the
who’s depressed thinks about death, so what you have been
onset of myocardial infarction in those with depression. The
thinking about death?’ I’m more likely to ask that question
cardiovascular risk associated with anxious distress may be
and expect more serious answers if the patient is severely
especially high. Almas et al,28 in a longitudinal cohort study,
anxious.” Further, he explained, measurement is a part of
found that DSM-5–defined anxious distress was associated
with a cardiovascular disease risk with an OR of 2.1, higher *Cases have been fictionalized and were provided by the meeting
than the OR associated with depression (OR = 1.9). participants to illustrate material discussed in the article.

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Table 1. Some Assessments Used in Measurement-Based Care of Major Depressive Disorder With Anxious Distress
Instrument Symptoms Rater No. of Items Scoring Information Comments
WHO-529 Depressive Clinician 5 >28 = clinically significant Useful for its focus on full functioning, eg, energy
depression level and purposefulness
PHQ-930,31 Depressive Self 9 5–9 mild, 10–14 moderate, Brief index of depression; can be used with GAD-7
15–19 moderately severe, in clinical practice to get a full picture of depression
20–27 severe depression and anxiety. Includes suicidality item
GAD-732 Anxious Clinician 7 0–5 mild, 6–10 moderate, Brief, well-validated anxiety scale; serves as a good

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11–15 severe anxiety measure of “psychic pain”
CUDOS-A8 Anxious Self 5 Total possible score of 20 New self-report scale assessing presence of DSM-5
(0 = very satisfied to 4 = very anxious distress specifier symptoms in the past week
dissatisfied for each item)
DADSI2 Anxious Clinician 5 Total possible score of 20 New clinician-administered scale assessing DSM-5
(severity of item in the past anxious distress specifier symptoms. Not yet in use
week rated 0–4) by discussants but may be a good screening option
Abbreviations: CUDOS = Clinically Useful Depression Outcome Scale, DADSI = DSM-5 Anxious Distress Specifier Interview, GAD-7 = Generalized Anxiety
Disorder 7-item scale, PHQ-9 = Primary Care Evaluation of Mental Disorders 9-item Patient Health Questionnaire, WHO-5 = 5-item World Health
Organization Well-Being Index.

effective clinical care regardless of whether the symptoms are WHO-5. The 5-item World Health Organization Well-
physical or mental: Being Index (WHO-5) is a short rating scale measuring
I would never treat a patient’s hypertension without measuring subjective well-being. The items consist of 5 positively
their blood pressure. And, of course, I would never get just a phrased statements (eg, “I have felt cheerful and in good
“clinical global impression” of their high blood pressure. If I’m spirits”) and are rated on a 6-point Likert scale based on
treating diabetes, I’m going to measure glycosylated hemoglobin the proportion of time, over the last 2 weeks, when the
and ask to see self-monitored blood glucose data. In the last 15 respondent would agree with the statement. The WHO-5
years, measurement has been the best help for me in improving has good validity as a depression screening measure.29 Drs
how I treat patients. Trivedi and Manning agreed that this scale was a meaningful
According to Dr Trivedi, the value of measurement tools assessment in clinical practice, particularly because of its
lies in the fact that they provide strong evidence regarding focus on elements important to patient functioning such as
symptoms, function, quality of life, and side effects so that energy, restfulness, and purposefulness.
the subsequent patient interview can be more focused, which PHQ-9. The Primary Care Evaluation of Mental Disorders
can improve quality of care and increase remission rates. 9-item Patient Health Questionnaire (PHQ-9)30 is a self-rated
Dr Thase noted that the most significant legacy of STAR*D depression measure that focuses exclusively on DSM-based
was perhaps its implementation of measurement-based symptoms.30 The frequency of 9 symptoms is rated on a scale
care: “Clinicians do pay attention to feedback that patients of 0 to 3: not at all, several days, more than half the days, and
aren’t getting better or are suffering from side effects. But if nearly every day, respectively, in the last 2 weeks. A follow-up
clinicians aren’t asking the questions, or if patients don’t have question inquires about the patient’s functioning. Katzelnick
the opportunity to let them know that things aren’t going et al31 demonstrated that the PHQ-9 allowed clinicians to
well, then the feedback doesn’t occur.” He also hoped that the successfully determine rates of response (defined as a score
APA practice guideline update will emphasize the importance < 10) and remission of depressive symptoms (score < 5) at 12
of measurement-based care in light of new evidence from and 24 weeks. Dr Manning mentioned that one advantage of
randomized controlled trials (RCTs). the PHQ-9 is that it allows for ongoing inquiry about thoughts
The shortage of primary care providers and the limited of death or distress.
time available for evaluation were cited as contributors to GAD-7. In clinical practice, the well-validated Generalized
underrecognition of anxiety, and Dr Weisler observed that Anxiety Disorder 7-item scale (GAD-7)32 is often used. Dr
symptoms are often not elicited or measured until the patient Manning mentioned that it has a large evidence base and is
is referred for psychiatric care. To assess at an earlier stage the screener used in his practice. The participants praised
whether a patient meets the anxious distress specifier criteria, it for being effective and specific. Each item represents
a brief and reliable measurement is needed, and Dr Manning an anxiety symptom, and patients indicate how bothered
felt that if a well-validated discriminatory scale for measuring they have been by the symptom over the last 2 weeks on a
anxious distress were available, primary care providers would scale of 0 to 3. Its advantages include its short length and
quickly adopt it. self-administered format. Dr Trivedi noted that the PHQ-9
and GAD-7 can be combined with a cognition measure to
Screening Tools for Clinical Settings comprise a full clinical picture of symptoms.
Several easy-to-administer, well-validated, and sensitive CUDOS-A. To devise a scale keyed specifically to the DSM-5
scales are available for measuring depressive and anxious anxious distress specifier, Zimmerman et al modified the
symptoms (Table 1). Clinically Useful Depression Outcome Scale to include items

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capturing the anxious distress specifier (CUDOS-A).8 This
CASE VIGNETTE 2
self-report scale consists of 5 items that correspond to the 5
Charlie, a 25-year-old man, presented in a primary care clinic
criteria in the anxious distress specifier, and each is rated on to obtain herpes prophylaxis. He was getting married soon and
a 5-point ordinal scale. Zimmerman et al demonstrated good also requested medication to help manage anxiety in relation
internal consistency, reliability, and validity,8 and advantages to the wedding. Charlie had recently returned from 2 tours of
include its brevity and self-administered format. While the duty in the Middle East, and though he had tried to make an
specifier requires anxiety symptoms to be present for the appointment in the VA system to address his anxious symptoms,
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majority of days during an episode, the CUDOS-A measures he had encountered great difficulty.
symptoms cross-sectionally, capturing only those present that The clinician administered the GAD-7, PHQ-9, and WHO-5
week. to get a complete picture of Charlie’s anxious and depressive
DADSI. Zimmerman and colleagues2 also developed symptoms and level of functioning. Charlie reported excessive
the DSM-5 Anxious Distress Specifier Interview (DADSI), worry and anxious symptoms as the primary cause of his
mental distress, but the assessments also indicated significant
a clinician-rated scale assessing the 5 symptoms in the
depressive symptoms, such as low mood and decreased energy
specifier. This scale inquires about the severity of symptoms
levels, that had emerged subsequent to the anxiety and required
over the past week as well as whether the symptoms have attention.
been present for the majority of the episode. In a sample
of 173 depressed patients from the Rhode Island Methods Charlie’s life situation should prompt a number of issues
to Improve Diagnostic Assessment and Services project, for the clinician to consider: How will his anxiety and mood
78% met criteria for the anxious distress specifier.2 The symptoms affect his new marriage? Will his wife be at greater
authors demonstrated reliability and validity and found risk of suffering interpersonal violence? If he has children, will
that the scale was sensitive to detecting improvement. Dr the quality of his parenting be affected, and will his children
Manning commented that the DADSI is still a new scale be more likely to develop mood or anxious symptoms,
and is unproven in broad practice in comparison to an as has been shown for symptomatology in mothers?20
These questions illuminate the possible consequences of
instrument such as the GAD-7. Although the participants do
not detecting and treating depression and anxiety. If the
not currently use the CUDOS-A or DADSI, they did praise
primary care clinician had not used a measurement-based
Zimmerman’s approach, and Dr Weisler mentioned that the care approach, employing 3 structured assessments, the
scale is quick to administer. patient’s significant depressive symptoms may have gone
unaddressed entirely.
Electronic Assessment
Dr Weisler mentioned an ongoing study with which he is
involved in which patients rate symptoms using their phones
via an app; not only is this convenient, but it allows clinicians
TREATMENT STRATEGIES
to more accurately and effectively track changes in depression
or anxiety symptoms. Dr Manning commented that, ideally, The participants emphasized that even if an
information on depressive and anxious symptomatology antidepressant is efficacious for a patient’s depressive
would be digitized and collected via a kiosk or a smartphone symptoms, his or her anxiety may not improve. The
app that would interface with the electronic health record to participants also recognized the importance of individual
minimize workload. patient characteristics and symptom profiles. Patients, as
Further, Dr Trivedi relayed that his group has developed well as their family members, may have received multiple
software called VitalSign6 to capture PHQ-9 and GAD-7 agents before, so the history of response should be
data.33,34 Designed for use in primary care, pediatric, and considered. Dr Weisler mentioned that pharmacogenomic
specialty clinics, the software collects data on symptoms, side testing may sometimes be of value in determining
effects, and adherence. Patients complete the measures on an which antidepressant and/or dose to use in ultrarapid
iPad. Dr Trivedi commented, “There is an indirect but a very or poor metabolizers (as well as whether l-methylfolate
solid benefit from these routinized itemized measurements— augmentation might be helpful, for example, in patients
patients become much more educated about what the goals with T or TT MTHFR alleles). Anxiety subtype also matters:
are, what the targets for their treatments are, and what they Dr Weisler commented that anxiety symptoms related to
are looking for in terms of improvement or lack thereof. You panic or obsessive-compulsive disorder or posttraumatic
can then target patients’ treatments to those goals, and this is stress disorder (PTSD) might lead him to choose a
closer to shared decision making.” Dr Trivedi also relayed an drug that is FDA approved or studied for treating those
insight from patient advisory focus groups: for some patients, disorders. In the case of PTSD symptoms, he might avoid a
self-rated symptom and side effect assessments may be more benzodiazepine, since lack of efficacy and problems related
effective than clinician interview in eliciting symptoms. to learning have been demonstrated in PTSD for that
“They feel pressured when a doctor is asking, ‘Well, how’s medication class.35 He also advised taking a few minutes to
your sleep? How’s your appetite?’ With a self-rated measure, assess for bipolarity by inquiring about personal or family
they are more relaxed and have more time available to history of mania/hypomania, earlier onset, and higher
answer. Patients appreciate that.” number of lifetime mood episodes and employing a simple

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reporting of 1 toPDF onAany
3 side effects.)
tool such as the Mood Disorder Questionnaire. Dr Weisler website.
distinct neurobiological
stated that his strategy for pharmacologic treatment of MDD profile in these patients (as demonstrated by Ionescu et al38)
with anxiety would be this: may be responsible for differences in side effect prevalence.
Adherence issues. The importance of ensuring medication
Step 1: Prescribe an SSRI or SNRI that has FDA approval
adherence was discussed; Dr Weisler remarked, “Adhering
both for anxiety and for MDD.
to treatment is one of the biggest problems that our patients
Step 2: Optimize the dose and duration of this treatment.
have. One of the advantages I’ve found in looking at a
If partial or nonresponse occurs…

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controlled drug registry is that, in addition to seeing other
Step 3: Add buspirone up to 60 mg/d (but not bupropion,
potential providers and drugs with abuse potential, I can find
due to increased initial anxiety).
out what pharmacies patients are using. I can then call their
If partial or nonresponse occurs…
pharmacy and see if the patient is filling other medical and
Step 4: Depending on the patient’s medical history and
psychiatric prescriptions. Anxiety can drive nonadherence,
anxiety severity, add a second-generation antipsychotic
partly because if a person is anxious and worried, they tend to
that has FDA approval for MDD.
be more forgetful.”
Dr Manning commented that if a major guideline (eg,
APA, CANMAT) were to recommend proven and efficacious Antidepressants
interventions for these patients, he would follow them. SSRIs. Selective serotonin reuptake inhibitors (SSRIs) are a
The 2016 CANMAT guidelines36 recommend choosing an mainstay of first-line pharmacologic treatment across different
antidepressant with efficacy in generalized anxiety disorder clinical guidelines for depression.25,36 For patients with
for patients with anxious distress, but this recommendation is anxious depression, though, SSRI monotherapy may prove
level 4 (expert opinion) evidence; the 2012 guidelines specific inadequate; Dr Manning noted that in many patients they are
to MDD with comorbid anxiety37 found no strong basis for only modestly helpful for anxiety. In level 1 of STAR*D, only
altering pharmacotherapeutic treatment in the presence 22% of patients with anxious depression reached remission
of anxiety. The 2009 APA guidelines25 predate the anxious with 12 to 14 weeks of citalopram monotherapy.13 Fava and
distress specifier. They do not substantially differentiate initial coworkers39 showed higher remission rates but no significant
treatment choice for patients with anxiety symptoms but do differences in efficacy or tolerability among fluoxetine,
mention a role for augmentation with benzodiazepines or sertraline, or paroxetine for acute treatment of MDD in
sedative hypnotics; neither is a level 1 (substantial clinical patients with anxious depression. Thaler and colleagues’40
evidence) recommendation. review of the literature also indicated a lack of difference
among second-generation antidepressants for these patients.
Special Considerations SNRIs. If monotherapy does not bring symptom relief,
Dosing. The APA and CANMAT practice guidelines tapering the medication and simultaneously titrating up
recommend lower starting doses with slow upward titration an antidepressant of a different class is a possible next step.
for patients with significant anxiety.25,37(p14) Dr Weisler felt that there is not much difference in efficacy
Tolerability/side effects. Asked which side effects might between the SSRIs and serotonin-norepinephrine reuptake
be particularly prevalent in patients with MDD and anxious inhibitors (SNRIs; venlafaxine, duloxetine) in treating anxious
distress, Dr Thase replied, “All of them.” He explained further: depression. A post hoc analysis found greater remission rates
“Think of the predisposition to anxiety as an amplifier in the at 6 weeks with venlafaxine versus fluoxetine41; however, a
limbic system of preoccupation and concern with distress. comparison of venlafaxine and sertraline showed similar
Any somatic cue is a potential danger signal. In studies of symptomatic improvement.42
depression—with all types of antidepressants—the anxious Bupropion. The recent large, multicenter Veterans Affairs
depressed patients nearly always have higher levels of a broad Augmentation and Switching Treatments for Improving
array of autonomic, gastrointestinal, and CNS side effects.” Depression Outcomes (VAST-D) trial43 showed a greater
Dr Weisler stressed the importance of weighing benefits incidence of anxiety with bupropion versus atypical
and drawbacks. In certain patients, oversedation may be an antipsychotic augmentation. Trivedi and colleagues,44
issue; in others, extrapyramidal symptoms may complicate however, showed comparable effectiveness of bupropion and
the picture. Gradual dose increases and close monitoring of sertraline in depressed patients with anxious symptoms, and
progress are key. the CANMAT guidelines36(p545) state no difference in efficacy
Chan et al,11 in the large Combining Medications to among SSRIs, SNRIs, and bupropion for anxious distress.
Enhance Depression Outcomes (CO-MED) study, found Antidepressant combination. No antidepressant is
higher side effect burden in depressed patients with anxiety approved by the US Food and Drug Administration
symptoms (P = .0009) even if they were not receiving higher (FDA) as combination therapy for treatment-resistant
doses. Gaspersz and colleagues14 found that patients with MDD; however, clinicians often combine antidepressants
the DSM-5 anxious distress specifier had a higher number as a second-step approach. The CO-MED study11,45
of side effects; 41% of those with the specifier had at least 4 evaluated first-step combinations of escitalopram + placebo,
side effects, versus only 20% of those without the specifier. escitalopram + sustained-release bupropion, and extended-
(Logistic regression revealed no effect of the specifier on release mirtazapine + venlafaxine for both acute (12-week) and

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1357   J Clin Psychiatry 78:9, November/December 2017
 Academic Highlights

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miles per hour. PDF on any
continuation (28-week) therapy. Across the treatment groups,
Covariate-adjusted website.
remission rates were
at 28 weeks, 44% of those with and 45% of those without 15.5% for lower-dose and 28.3% for higher-dose exercise
anxious features achieved remission. The authors found no augmentation, leading to an NNT of 7.8. Trivedi et al48 point
association between presence of anxious features at baseline out that remission rates with exercise are comparable to those
and differential treatment outcomes among the treatment seen with an SSRI/bupropion combination and that their
groups.11 CO-MED found no advantage for antidepressant results are within the range of findings that warrant change
combination as first-line therapy (bupropion + escitalopram or in clinical practice. According to Dr Trivedi, for a person
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mirtazapine + levofloxacin) versus escitalopram alone,45 only a weighing about 80 or 90 kg, about 1,200–1,400 calories
greater side effect burden. Dr Thase commented, though, that of energy expenditure per week is needed to see an effect.
combinations might be useful for certain subsets of patients, This translates to 40–45 minutes of moderate to vigorous
such as those with greater severity of symptoms or treatment exercise 3 times per week. The rigor of the exercise should
resistance. be significant, and the patient should not be able to have a
conversation when exercising. Heart rate should be about 80%
Nonpharmacologic Strategies of the maximum rate for the patient’s age.
CBT. Cognitive-behavioral therapy (CBT) may be used as Relaxation exercises and good sleep hygiene. Echoing
a first-line treatment for MDD,25(p17) particularly in patients earlier points about sleep, Dr Weisler said that he has found
who express a preference for it. It may be used instead of or in sleep hygiene recommendations, as well as relaxation
addition to pharmacotherapy. At level 2, STAR*D found no exercises, to be useful for many patients. He noted that
significant differences in response and remission outcomes resources in these areas are freely accessible to patients
with CBT, as either monotherapy or adjunctive treatment, from a number of online providers and that they can make
versus pharmacotherapy alone. Time to remission was greater a substantial difference. He also mentioned the value of
with CBT augmentation than with medication augmentation assessing for and treating sleep apnea because of its link with
(55 vs 40 days) but did not differ for switching to CBT depression.49
versus switching to medication.46 A subanalysis comparing
patients with anxious and nonanxious depression47 showed Augmentation Strategies
no significant interaction between anxious depression and It was noted that the poorer prognosis associated with
treatment assignment, but significantly lower response anxiety symptoms demands a greater need to combine
rates were seen for anxious depression versus nonanxious different treatment modalities. If a patient does not respond
depression in the CBT switch group (14% vs 36%), and lower to initial treatment of optimal dose and duration, or if
remission rates were seen in both the switch (21% vs 51%) residual symptoms are present, augmentation strategies
and augmentation (14% vs 38%) groups. involving a medication targeting another neural circuit can be
Two or 3 hours of therapist time spread over 6 weeks was considered.
recommended by Dr Thase for achieving optimal results, and Atypical antipsychotics. At present, 3 atypical
he commented that therapist engagement is important even if antipsychotics are FDA-approved for adjunctive use in
therapy is delivered electronically: “Depression undermines treatment-resistant MDD: aripiprazole, brexpiprazole, and
the ability to learn new material, focus on it, and follow extended release quetiapine (quetiapine XR). A fourth
through with the practice. Evidence-based psychotherapy can agent, olanzapine, is approved for use in treatment-resistant
be learned online, but without the therapist’s guidance and MDD in combination with fluoxetine. Meta-analyses have
encouragement, the book often goes ‘unopened,’ so to speak.” demonstrated greater efficacy of these medications versus
Dr Trivedi relayed that as part of the VitalSign6 quality placebo as augmentation in patients with treatment-resistant
improvement project, his group recently completed a study34 MDD. Nelson and Papakostas50 found ORs of 1.69 and 2.00
evaluating the outcomes of 8 sessions of behavioral activation for response and remission, respectively; Spielmans et al51
delivered through teletherapy. The sample consisted of 74 also showed statistically significant effects on response and
low-income primary care patients with moderate depressive remission rates as well as clinician-rated depression severity
and anxious symptoms. The majority of patients who received measures.
at least 1 therapy session achieved depression remission, Aripiprazole. Trivedi et al52 demonstrated efficacy of
and patients completing at least 4 sessions demonstrated adjunctive aripiprazole in a pooled analysis of two 14-week
substantial decreases in depression (median PHQ-9 score studies that included patients who had shown nonresponse
decrease of 10.0) and anxiety (median GAD-7 score decrease to 1 to 3 previous antidepressant trials. Both the anxious and
of 8.0) symptoms at the final session. nonanxious depression groups showed greater improvement
Physical exercise. The participants agreed that physical in MADRS total score with aripiprazole versus placebo
exercise can be an effective adjunct, and Dr Weisler pointed (decreases of 8.72 and 8.61 in the anxious and nonanxious
to Dr Trivedi’s contributions in this area. In a sample of groups, vs 6.17 and 4.97 with placebo). Additionally, the
sedentary individuals with SSRI-resistant MDD, Trivedi and VAST-D study43 demonstrated a significantly better remission
colleagues48 compared two 12-week exercise interventions rate for augmentation with aripiprazole versus switching
with energy expenditures equivalent to walking 210 minutes to a different antidepressant (relative risk = 1.3; P = .02).
per week at 4 miles per hour or 75 minutes per week at 3 Akathisia has been reported as the most common adverse

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J Clin Psychiatry 78:9, November/December 2017   1358
Academic Highlights

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event with aripiprazole.53 Trivedi and colleagues52 showed
Figure 3. Remission Rates With Antidepressant Treatment in
that although discontinuation due to adverse events was low, Anxious vs Nonanxious Depressiona
and aripiprazole was generally well tolerated, it was associated
with a higher rate of akathisia (24.6%) than placebo (4.4%). STAR*D Level 2
100
Brexpiprazole. Drs Weisler and Thase pointed to a Anxious MDD
40 *
post hoc analysis of 2 RCTs7 that indicated efficacy for Nonanxious MDD

Remission by HDRS Criterion, %

* *
*
brexpiprazole in MDD patients who had nonresponse to 35

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antidepressant monotherapy. McIntyre et al7 defined anxious 30 *
distress using proxies for DSM-5 criteria, and 55% of the 25
sample met the criteria.The studies compared brexpiprazole 20
at doses of 1, 2, and 3 mg and placebo as adjuncts to 15
antidepressant treatment. Brexpiprazole showed greater 10
improvement than placebo on MADRS score change at week
5
6 in patients both with and without anxious distress; in the
0
anxious distress group, the least squares (LS) mean difference

pr tat am

sp ati m
n

in
lin
io

Bu ent pra
in MADRS score change was –2.95 vs placebo (P = .002) with

io n

iro on
ax

Bu en opr
a
op

op io
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ith m lo
af

ne
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ith m al
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W g ita
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the 2-mg dose. An RCT54 in antidepressant nonresponders

W ug it
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yielded similar findings; the LS mean difference in MADRS

A
score from placebo for brexpiprazole at week 8 was –2.98 in
patients with anxious distress (P = .0099). Moderate weight aReprinted with permission from Thase63; data from Fava et al.13
*P < .05.
gain and akathisia are reported with brexpiprazole.55 Abbreviations: HDRS = Hamilton Depression Rating Scale,
Quetiapine XR. Bandelow et al56 investigated efficacy of STAR*D = Sequenced Treatment Alternatives to Relieve Depression.
quetiapine XR at 150-mg and 300-mg doses as adjunctive
therapy in a pooled analysis of two 6-week RCTs. When
anxious depression was defined as a HARS score ≥ 20, symptoms of anxiety as well as depression, and he felt that
significant MADRS score reductions vs placebo at week the published data on metabolic issues have not affected
6 were found for both doses in those with nonanxious practice much. He advises primary care and mental health
depression, but only for the 300-mg dose in those with care providers to obtain a comprehensive metabolic panel,
anxious depression. With an HDRS anxiety/somatization lipid panel, and hemoglobin A1c measurement at the start
score ≥ 7 as the definition, MADRS score reductions were of therapy, to repeat those measurements within 3 months,
significantly greater for both doses starting at week 1 (week 6: and, depending on the results, to obtain them thereafter
150 mg/d, P < .01; 300 mg, P < .001) in patients with anxious every 6 months to once per year. He explained why: “The
depression, but for neither dose in those with nonanxious connection between depression and cardiovascular health
depression. Adverse events commonly associated with and the importance of treating depression in cardiovascular
quetiapine are weight gain, metabolic disturbances, and patients demands that we monitor for ways we might be
sedation.57 worsening a patient’s metabolic status, and this must be
Olanzapine. Data specifically on olanzapine and anxious balanced for each individual.” Dr Weisler pointed out that
depression are lacking. In a 12-week study,58 olanzapine/ efficacy must be balanced with side effect risk, citing a
fluoxetine combination (OFC) was associated with rapid meta-analysis50 of atypical antipsychotic augmentation
antidepressant effect and improvement in depressive that showed a higher remission rate for these agents versus
symptoms compared with antidepressant monotherapy in placebo (pooled rate of 30.7% vs 17.2%; P < .00001), but
MDD patients during the first 6 weeks of treatment, but at also a higher rate of discontinuation due to side effects
study endpoint, the groups were not significantly different. (OR = 3.91; P < .00001). Therefore, it is important to monitor
Two other large 8-week studies compared OFC to olanzapine the effects of treatment, including clinical improvement and
and fluoxetine monotherapies in nonresponders to fluoxetine adverse events, to optimize response and adherence in each
monotherapy.59 One study showed no significant between- individual.
therapy difference in MADRS score change; however, the Buspirone. Buspirone enhances SSRI activity through
pooled analysis showed a remission rate of 27% for OFC (vs the 5-HT1A receptors61 and is FDA-approved for short-term
17% and 15% for fluoxetine and olanzapine monotherapies), treatment of anxiety symptoms. Physical dependence is not
as well as a shorter time required for 25% of patients to a concern.62 Level 2 of STAR*D compared bupropion versus
achieve therapeutic responder status (30 days with OFC vs 55 buspirone as augmentation of citalopram following initial
and 53 days for fluoxetine and olanzapine monotherapies). nonresponse to monotherapy and found remission rates
Somnolence, sedation, and weight gain are commonly of 36.7% and 39.2%, respectively, in nonanxious patients;
observed with olanzapine.60 however, in those with anxious depression, the rates were
Use in clinical practice. Dr Manning commented that he only 17.9% and 9.2% (Figure 3).13,63 Dr Trivedi called
has seen an increase in prescription of second-generation the results surprising, in that the investigators expected
antipsychotics among primary care providers for treating to find that buspirone would be superior in anxious

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1359   J Clin Psychiatry 78:9, November/December 2017
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depression—this was not the case, and remission rates in
CASE VIGNETTE 3
those with anxious symptoms were startlingly low with either
Lucille, a 62-year-old woman, presented with a major depressive
agent. According to Dr Trivedi, the findings demonstrated episode and had long struggled with recurrent depression.
the existence of “a subgroup of patients who have significant The current episode had begun 4 weeks before with no clear
anxiety and meet the criteria for the anxious depression precipitants, although relationship stress had been associated with
specifier and who don’t do well on monoaminergic agents— prior recurrences. Her youngest child had recently left for college.
this is true for any of the antidepressants.” Lucille had a markedly depressed mood and had withdrawn
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Benzodiazepines. Although benzodiazepines do from many activities, though she continued going to work. Her
not treat depressive symptoms, they are often used as concentration was so poor that she struggled even to read the
newspaper, and her energy was low. Her sleep was disrupted, with
augmentation for anxiety and/or sleep problems. The
initial insomnia of 2–3 hours, frequent awakenings, and total
APA Practice Guideline25(p19) includes them as an option
sleep time averaging 5 hours. She noted decreased appetite and
that “may be recommended on the basis of individual felt persistent nervous tension and restlessness. Lucille sometimes
circumstances” if anxiety or insomnia is prominent. This fretted that she had not been a good enough mother, but she
course of action would follow first trying SSRI or SNRI also noted that these feelings were excessive. Panic-like feelings
monotherapy. Short-term use (ie, < 4 weeks) in combination occasionally occurred, with no full panic attacks, and she at times
with an antidepressant has been shown to lessen anxiety.64 experienced rapid heart rate and shortness of breath, especially
However, their effectiveness must be balanced against the when thinking about her children. Lucille felt a deep pessimism
abuse potential. Dr Thase recommended making, at the about her future but denied suicidal ideation. Scales were used to
quantify her symptoms; she scored a 31 on the MADRS and a 24 on
outset, a commitment with the patient to soon taper the
the HARS, and her Clinician Global Assessment was “markedly ill.”
benzodiazepine dose and find other combination strategies.
In older patients, benzodiazepines can present an elevated Because previous venlafaxine treatment had been
fall risk, but Dr Thase did not believe that they act as an unsuccessful for Lucille, sertraline was chosen and titrated to 200
accelerant of dementia—rather that unremitting anxiety mg, then decreased to 150 mg due to lethargy. After some initial
is a more likely accelerant. Dr Weisler agreed, noting that improvement, at the second month her PHQ-9 score was 21, and
for some patients, lack of sleep can be another aggravating her GAD-7 score was 14. A Clinical Global Assessment indicated
factor for dementia. Overdose dangers were discussed, and she was still “moderately ill.” The physician decided to augment
Dr Manning cited concerns among primary care clinicians with brexpiprazole, beginning at 0.5 mg and titrated to 2 mg
over 2 weeks. The decision to augment rather than increase the
about prescribing benzodiazepines, as well as a focus on
sertraline dose was related to gastrointestinal and libido-related
limiting exposure to the short term. Dr Weisler noted that
side effects, as well as a previous SNRI failure. After 3 weeks with
many patients with depression and anxiety take opioids and augmentation, her MADRS score dropped to 12, and her HARS
that the combination with benzodiazepines can be dangerous, score was 7. By week 14 (6 weeks with augmentation), Lucille
possibly leading to difficulty breathing or even death. Use was very much improved. Her Clinician Global Assessment
of prescription drug monitoring programs and electronic was rated as “normal”; her self-rated PHQ-9 score was 3, and
health records has been suggested as a way to help clinicians her GAD-7 score was 2, also well within the normal range. She
identify risky use of these medications.65 Dr Weisler cited a tolerated the medications well, with only brief, mild restlessness
recent report66 that the 16% of Americans who have mental that began when the brexpiprazole dose was raised to 2 mg
and then resolved over the next week. Because Lucille had
health disorders receive over half of all opioids prescribed
experienced multiple previous episodes, she remained on
in the United States, as well as data showing that 30% of
combination therapy while being monitored for adverse events.
individuals dying due to opioid-related causes in 2010 also
had benzodiazepines in their system.65 He emphasized that
improving pain management in this population is critical to
reduce opioid dependency.
ADOPTION OF THE SPECIFIER IN
Other medications. Thyroid hormone supplementation
may be useful in some patients with treatment-resistant
CLINICAL SETTINGS
depression; evidence in the literature is mixed.67 Lithium The participants felt that the anxious distress specifier
is another augmentation option, with a meta-analysis68 has yet to be fully adopted in clinical settings. Dr Thase
confirming its effectiveness. A third option is l-methylfolate, commented that physicians have long been frustrated by the
which is well tolerated and also may be useful in some fact that they were making multiple diagnoses in a single
patients.69 patient with this symptom profile, and the specifier can
In patients with sleep problems, nonbenzodiazepine serve as a way for a clinician to describe whether a patient’s
sedative hypnotics such as eszopiclone, zaleplon, and presentation of depressive disorder includes more or less
zolpidem may be helpful as augmentation and present less anxiety.
potential for dependence than benzodiazepines. Fava et al70 From the primary care perspective, Dr Manning said
showed significant reductions in total HDRS-17 score and that although physicians are not yet generally aware of the
insomnia severity, though not in HDRS anxiety/somatization specifier, it describes a common patient profile long seen in
score, in MDD patients with anxious symptoms receiving clinical practice. He doesn’t differentiate between it and the
eszopiclone with an SSRI. prior concept of “anxious depression.” He also observed that

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the specifier has not yet gained enough momentum to be
be targeted to specific on any and thewebsite.
anxiety specifier
included in ICD-10. (ICD-10’s most similar diagnosis, “mixed group may be one that needs more aggressive treatment.” He
anxiety and depressive disorder,” requires the presence of mild also thought that efforts toward adapting remission criteria to
symptoms of both anxiety and depression that do not meet include improvement in anxious distress would be useful.
the severity threshold for either disorder.71) The participants expressed enthusiasm about the
potential for future research on MDD with anxious distress
and called for studies that, by virtue of their design, would
ASSESSING RESPONSE AND REMISSION

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focus purely on the anxious distress specifier (rather than
Outcomes in MDD can be categorized in 5 ways: response, measuring a “pseudospecific” effect on anxiety); for example,
remission, recovery (sustained remission), relapse (emergence randomization could be stratified based on the presence of the
of an episode during remission), and recurrence (emergence specifier. Such efforts could then help the field move toward
of an episode during recovery). Achieving remission is the discovering the optimal treatments to provide relief for these
main goal of MDD treatment.72 Measurement-based care patients.
for pursuing remission involves regular use of tools such as Published online: November 28, 2017.
those described in the Screening and Measurement section.
Their value lies partly in the existence of a large body of REFERENCES
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