anxious distress predicts subsequent 3.pdf · 52 | chapter 3 abstract introduction: evidence has...

Roxanne Gaspersz, Femke Lamers, Justine M. Kent, Aartjan T.F. Beekman, Johannes H. Smit, Albert M. van Hemert, Robert A. Schoevers,

and Brenda W.J.H. Penninx.

Published in Journal of Psychiatric Research 2017; 84: 41-48

Anxious distress predicts subsequent treatment outcome and side effects

in depressed patients starting antidepressant treatment

52 | Chapter 3

Abstract

Introduction: Evidence has shown that the DSM-5 anxious distress specifier captures a clinically valid construct that predicts a worse clinical course. Although of importance for treatment planning and monitoring, however, the specifier’s ability to predict treatment outcome is unknown. This is the first study to examine the ability of the DSM-5 anxious distress specifier to predict treatment response and side effects in depressed patients who recently initiated antidepressant treatment.

Methods: Patients were from the Netherlands Study of Depression and Anxiety, an ongoing longitudinal cohort study. Baseline, 1- and 2-year follow-up data were used from 149 patients (18–65 years) with current Major Depressive Disorder (MDD) who recently started adequately dosed antidepressant medication. Five self-report items were used to construct the DSM-5 anxious distress specifier. Treatment outcomes were depression severity after 1 year and 2 years, remission of MDD after 2 years and antidepressant side effects during treatment. For comparison, analyses were repeated for comorbid DSM-IV-based anxiety disorders as a predictor.

Results: In depressed patients who received antidepressant treatment, the anxious dis-tress specifier (prevalence=59.1%) significantly predicted higher severity (1 year: B=1.94, P=0.001; 2 years: B=1.63, P=0.001), lower remission rates (OR=0.44, P=0.0496) and greater frequency of side effects (≥4 versus 0: OR=2.74, P=0.061). In contrast, the presence of comorbid anxiety disorders did not predict these treatment outcomes.

Conclusion: The anxious distress specifier significantly predicts poorer treatment outcomes as shown by higher depression severity, lower remission rates, and greater fre-quency of antidepressant side effects in patients with MDD on adequate antidepressant treatment. Therefore, this simple 5-item specifier is of potential great clinical usefulness for treatment planning and monitoring in depressed patients.

Keywords: anxious distress; DSM-5 anxious distress specifier; Major Depressive Disorder; anxiety disorders; treatment response; Epidemiology.

Anxious distress in depression predicts subsequent treatment outcome and side effects | 53

3

Introduction

Major Depressive Disorder (MDD) is among the most disabling disorders worldwide [1,2], yet the heterogeneity of the MDD diagnosis has not been reflected in approaches to clas-sification, diagnosis and treatment [3-5]. A body of evidence has underscored the clinical importance of the concept of anxious depression, as it is associated with greater symp-tom severity, chronicity of MDD and greater functional disability [6]. Moreover, anxious depression was found to be associated with poorer treatment outcomes [7-11] and with a higher rate and burden of side effects [8-10], although these results were not found in all studies [12-14]. A review by Ionescu and colleagues suggested that anxious depression is more difficult to treat [10]. This may be the result of an underlying differential biological profile of anxious depression [15] or due to trait anxiety which is difficult to treat with current interventions. The lack of a uniform definition of anxious depression in the liter-ature has made comparisons of results across studies difficult. However the introduction of the anxious distress specifier in DSM-5 [16] may help overcome this problem.

Two studies have shown that the DSM-5 anxious distress specifier is a reliable and valid measure, with significant discriminant and convergent validity [17,18]. Our previous work has shown that the specifier is longitudinally predictive of a worse clinical course and outcomes in a large cohort of depressed persons. Furthermore, it has shown that the specifier outperforms comorbid DSM-IV-based anxiety disorder diagnoses as a longitu-dinal predictor [18]. Since the introduction of the anxious distress specifier, no studies have evaluated whether depressed patients meeting the DSM-5 specifier have differential treatment response. If the specifier is found to be predictive of worse treatment outcomes, then it is of great clinical usefulness for treatment planning and monitoring in depressed patients with significant anxiety.

Our previous work aimed to test the longitudinal validity of the DSM-5 anxious distress specifier and validated it against DSM-IV-based comorbid anxiety disorder diagnoses in a large cohort of depressed persons (N=1,080) regardless of treatment status [18]. We now aim to examine whether the DSM-5 anxious distress specifier predicts treatment outcomes and frequency of side effects in a group of patients with MDD on recently ini-tiated adequate antidepressant treatment, and how the predictive validity is compared to that of comorbid DSM-IV-based anxiety disorders.

54 | Chapter 3

Methods

Study SampleParticipants were selected from The Netherlands Study of Depression and Anxiety (NESDA) [19], an ongoing longitudinal cohort study designed to examine the long-term course of depressive and anxiety disorders. A total of 2,981 participants (18–65 years) were included in the baseline assessment (2004—2007), consisting of healthy controls (n=652; 22%) and participants with a past or current depressive and/or anxiety disorder (n=2,329; 78%). Recruitment took place in the community (19.0%), primary care (54.0%), and specialized mental health care settings (27.0%), reflecting different settings and stages of psychopathology. Uniform inclusion and exclusion criteria were used. Patients with an age of 18 through 65 years were included. Patients with a primary clinical diagnosis of a psychiatric disorder other than depressive or anxiety disorders, and those not fluent in Dutch were excluded. At baseline and at 2-year follow-up (n=2,596; 87.1%), data were obtained by trained research staff during a broad assessment, consisting of a face-to-face interview, self-reported questionnaires, a medical examination and cognitive computer tasks. In addition, antidepressant medication use was recorded based on inspection of participants’ prescription drug containers, which were brought to the interview (75.2%, n=112 patients). Only when drug containers were not brought in, did we rely on self-re-port (which, if felt necessary, was also re-checked by later inspection of drug container labels during phone contact). In the Netherlands, all drug containers are provided with a registered label that shows the patient’s name, the prescriber name, frequency and dose of the drug as a standard procedure by all pharmacies. Data of 1-year follow-up (n=2,445; 82.0%) were acquired by a self-reported questionnaire including measures of depression symptom severity and medication use. The research protocol was approved by the Ethical Committees of all participating universities and all participants provided written informed consent after the study procedures were fully explained. The rationale, objectives and recruitment strategy of the NESDA study can be found elsewhere [19].

We aimed to include patients with new-onset MDD episodes and a recent start of anti-depressant treatment to optimally determine treatment outcomes. We achieved this by carefully selecting timeframes to include patients who are most likely to meet these criteria. First, we selected patients with a current diagnosis of MDD (defined by the 6-month recency criteria on the CIDI assessment) at baseline. Second, of these current cases, we selected only patients who a) recently started around baseline (but were not on medication long enough to expect a therapeutic effect at baseline) or b) started anti-depressant treatment in the period from baseline to 2-year follow-up. Third, we included only patients with an adequate dose and duration of use (i.e. an adequate Defined Daily Dose [DDD] of ≥1 and a minimum duration of antidepressant use of ≥3 months; see also next section), in order to insure selection of patients for whom a therapeutic effect


3

could be expected (Supplementary Figure S1). At baseline and follow-up, the Composite International Diagnostic Interview (CIDI) version 2.1 [20] was used to assess a diagnosis of MDD according to DSM-IV algorithms. At each assessment, medication was coded according to the Anatomical Therapeutic Chemical (ATC) classification [21]. Antidepres-sants were classified as selective serotonin reuptake inhibitors (SSRI, ATC-code N06AB), tricyclic antidepressants (TCA, ATC-code N06AA) and other antidepressants (Other AD, ATC-code N06AF/N06AG/N06AX). Antidepressant dosages were expressed in World Health Organization (WHO) DDD, which is the assumed average maintenance dose per day for a drug used for its main indication in adults [22]. Duration of antidepressant use was assessed in months between baseline and 2-year follow-up.

Adequate antidepressant treatment was defined as frequent use of an antidepres-sant with a DDD of ≥1 and a total duration of antidepressant use of ≥3 months in the period around baseline to 2-year follow-up. Patients who already fulfilled the duration criterion (i.e. ≥3 months) for the adequate antidepressant treatment definition at base-line were excluded from the analyses, as treatment outcome is most reliably evaluated among patients who recently initiated treatment. By using this approach, all long-term antidepressant users were excluded, as well as patients with suboptimal dosages of antidepressants, for whom treatment outcomes cannot be interpreted accurately. Fur-thermore, the recent onset of both the MDD episode and the start of treatment make the assumption that the antidepressant medication was prescribed specifically for that par-ticular MDD episode fairly strong. We were then able to optimally determine treatment outcomes subsequently in a group of patients with depression who recently initiated antidepressant medication at an adequate dose.

Of the 2,981 participants included in the NESDA study, 1,115 participants had a current (past 6 months) MDD diagnosis at baseline, of which 1,090 participants had enough information present to construct the anxious distress specifier. Of these 1,090, 53.3% (581 persons) frequently used an antidepressant in the period from baseline to 2-year fol-low-up. Three hundred fifty-one of these patients already met the duration criterion of ≥3 months of antidepressant treatment at baseline (and thus were considered long-term users) and were therefore excluded. Of the remaining 230 patients, 168 patients initiated adequate antidepressant treatment between baseline and 2-year follow-up and met all inclusion criteria of this study. Of these, 19 patients had missing follow-up data, leaving a total of 149 eligible patients for the analyses (Supplementary Figure S1). In these 19 excluded patients with missing follow-up data, presence of the specifier was higher (84.2% versus 59.1%, P=0.034) than in included persons, but did not differ in other important baseline characteristics (age, gender, years of education, depression severity, AD class, AD duration of use, presence of any anxiety diagnosis).

56 | Chapter 3

Anxious distress specifier and anxiety disorder diagnosesThe DSM-5 anxious distress specifier was constructed using five items from the Inventory of Depressive Symptomatology (IDS) [23] and the Beck Anxiety Inventory (BAI) [24]. These items directly matched with the DSM-5 criteria for the anxious distress specifier: 1) feeling keyed up or tense (IDS item 7), 2) feeling unusually restless (IDS item 24), 3) difficulty concentrating because of worry (IDS item 15), 4) fear that something awful might happen (BAI item 5), and 5) feeling that the individual might lose control of him-self or herself (BAI item 14). The presence of the specifier was assessed according to the criterion of the DSM-5, requiring that a participant endorses at least 2 of the 5 symptoms. In addition to this dichotomous indicator of the specifier (present or absent), we also examined the number of specifier criteria endorsed (continuous indicator; range, 0–5). The construction of the anxious distress specifier is described in more detail in our pre-vious paper [18]. Anxiety disorder diagnoses were determined in the CIDI interview [20] and assessed Social Phobia, Panic Disorder with and without Agoraphobia, Agoraphobia, and Generalized Anxiety Disorder. We assessed the presence of any current (past 6 months) anxiety disorder (dichotomous indicator) and the number of anxiety disorders (contin-uous indicator; range, 0–3).

Treatment outcomesOutcomes in this study were depression severity, remission, and side effects of antidepres-sant treatment. Depression severity was evaluated by the Quick Inventory of Depressive Symptomatology (QIDS) [25] at the 1- and 2-year follow-up assessment. The QIDS is a shortened, 16-item version of the IDS (range, 0–27) of which the overlapping specifier items (IDS items 7, 15, and 24) used to construct the specifier were excluded because this may cause overestimation of the outcome, leaving 14 items that covered only the domains for depression. The original algorithm for scoring was followed and resulted in a total score ranging from 0-24. For remission, we used the absence of a current (past month) diagnosis of MDD at the 2-year follow-up as assessed by the CIDI [20]. Side effects of antidepressants were measured in the period from baseline to 2-year follow-up and were assessed by the short 12-question Antidepressant Side Effect Checklist (ASEC-12) which measures patient-perceived side effects including insomnia, sleepiness during the day, restlessness, muscle spasms/twitching, dry mouth, profuse sweating, sexual disorders, nausea, constipation, diarrhea, weight gain and dizziness. The ASEC-12 is a shortened version of the self-report ASEC-21, which was recently validated against the psychia-trist-rated UKU Side Effect Rating Scale [26] and showed that the UKU had no predictive value above the self-report ASEC [27]. Since the number of side effects was non-normally distributed, we examined this as a categorical variable (‘0 side effects’, ‘1–3 side effects’ and ‘≥4 side effects’) similarly to Bet and colleagues [28].


3

CovariatesWe adjusted for sociodemographic characteristics, including sex, age and years of education and adjusted for severity in an additional step. It is debatable whether it is necessary or not to also adjust for depression severity. One can argue that patients with MDD who also suffer from concurrent anxiety already have a higher depression severity and that anxiety is more likely to be an epiphenomenon of the more severe forms of MDD, rather than a distinct phenomenon [8]. Because this is a speculation and adjusting for severity might be considered as overcorrection, we adjusted for depression severity in an additional step. For severity, we used the number of DSM-IV criteria of MDD (range, 5–9), rather than for example IDS score, because this has the least overlap with the construct of the anxious distress specifier, and is also a more clinical approach.

We previously [28] found that higher side effect reporting was associated with depression severity, higher dose of antidepressants (expressed in DDD) and TCA use, and that older age, concurrent benzodiazepine use and longer duration of antidepressant use was associ-ated with lower side effects reporting. Since severity—but not the other indicators—was significantly different among patients with and without the specifier, we additionally corrected for this variable in the side effects analyses.

Statistical analysisSociodemographic and depression characteristics and anxiety diagnoses at baseline were compared between patients with and without the specifier in the sample using Chi-square analyses for dichotomous variables, t-tests for continuous variables and nonparametric tests (Mann-Whitney U) for non-normally distributed variables. Cohen’s κ was calculated to assess overlap of the specifier and comorbid DSM-IV-based anxiety disorders in this sample.

For severity of MDD over time, we used linear regression analyses and for remission we used logistic regression analyses. To examine the number of antidepressant side effects, we used multinomial logistic regression analyses. For all three outcomes, three models were analyzed. Model 1 analyzed the specifier alone. Model 2 analyzed comorbid DSM-IV-based anxiety disorder diagnoses alone. Model 3 analyzed the specifier and DSM-IV-based anxiety disorder diagnoses in one model. All models were conducted for both the dichot-omous and continuous indicator of the specifier and for DSM-IV-based anxiety disorders. All analyses for all three outcomes were first adjusted for age, gender and educational years, and then additionally adjusted for depression severity at baseline. We checked for multicollinearity in linear models; no multicollinearity was detected (all variance inflation factors were below 1.6).

Statistical analysis was conducted with SPSS, version 21 (IBM Corp: Armonk, New York). All statistical tests were two-tailed, with the significance threshold set at 0.05.

58 | Chapter 3

Results

Study sample characteristics In the group of patients with MDD on adequate antidepressant treatment, the anx-ious distress specifier was present in the majority of patients (59.1%). Patients with and without the specifier did not significantly differ in sociodemographic and clinical char-acteristics, except for one year less education and higher depression severity in patients with the specifier (Table 1). Antidepressant type and duration of use were also comparable among patients with and without the specifier. In line with earlier results [18], we found that overlap between the anxious distress specifier and anxiety disorders in our sample was not very large (Cohen’s κ=0.10): 79.5% of patients with the specifier suffered from any comorbid anxiety disorder, versus 45.9% without the specifier (P<0.001).

Depression severity and remission Figure 1A shows that MDD after 2 years is more likely to remain present in patients with the specifier than in patients without the specifier (43.2% versus 21.3%, P=0.006). In our sample, the DSM-5 anxious distress specifier significantly predicted poorer treatment outcomes, as based on greater severity of symptoms at follow-up (Table 2) as well as lower remission rates at 2 year follow-up (Table 3). The anxious distress specifier pre-dicted higher depression severity at both 1- (P=0.001) and 2-year follow-up (P=0.001). In contrast, these analyses found no effects at all for comorbid anxiety disorders on sever-ity at follow-up (QIDS after 1 year: P=0.829; QIDS after 2 years: P=0.970; Table 2). When the analyses were repeated for the continuous indicators of the specifier and anxiety disorders, similar results were obtained (Table 2). Furthermore, the specifier predicted lower remission rates better than did comorbid DSM-IV-based anxiety disorders (Table 3). When both indicators were compared in one model (Table 3, model 3), predictive effects were still significant for the specifier (P=0.0496), but not for anxiety disorders (P=0.681). When the analyses were repeated for the continuous variants of both the specifier and anxiety disorders, similar results for the specifier were found with the continuous anxious distress indicator being more predictive than the number of anxiety disorders indicator in all three models (Table 3).

Side effects of antidepressantsPatients with anxious distress had a higher number of side effects compared to those without the specifier (≥4 side effects: 41.0% versus 20.0%, P=0.03) (Figure 1B).


3

Table 1. Sociodemographic and clinical characteristics in persons with and without the anxious distress specifier with MDD on adequate antidepressant treatment (N=149).

With anxious distress specifier

n=88

Without anxious distress specifier

n=61

Pa

Socio-demographic characteristics

Age, years, mean ± SD 39.7 ± 12.6 38.4 ± 11.6 0.532

Gender, female, n (%) 56 (63.6) 37 (60.7) 0.712

Education, years, mean ± SD 11.1 ± 3.4 12.3 ± 3.1 0.023

Clinical characteristics depression

Depression type, recurrent, n (%) 43 (48.9) 35 (57.4) 0.306

Severity, Number of DSM MDD criteria, mean ± SD 9.0 ± 0.9 7.5 ± 1.2 0.001

QIDSb at baseline, mean ± SD 6.9 ± 3.0 4.3 ± 2.4 <0.001

QIDSb after 1 year, mean ± SD 5.2 ± 3.0 3.0 ± 2.7 <0.001

QIDSb after 2 years, mean ± SD 4.7 ± 3.0 2.8 ± 2.1 <0.001

Age at onset, years, median (IQR) 22.0 (16.0–35.0) 25.0 (17.8–34.5) 0.455

AD medication, n (%)

SSRI 63 (71.6) 46 (75.4) 0.717

TCA 6 (6.8) 5 (8.2)

Other AD 19 (21.6) 10 (16.4)

Duration AD use during FU, months, median (IQR) 18.0 (8.0–24.8) 18.0 (9.0–23.0) 0.869

Anxious distress specifier and anxiety diagnoses

Presence of anxiety disorder(s)c

Social Phobia 44 (50.0) 10 (16.4) <0.001

Panic Disorder with Agoraphobia 25 (28.4) 7 (11.5) 0.013

Panic Disorder without Agoraphobia 14 (15.9) 7 (11.5) 0.444

Agoraphobia 10 (11.4) 0 (0.0) 0.006

Generalized Anxiety Disorder 37 (42.0) 11 (18.0) 0.002

Any, n (%) 70 (79.5) 28 (45.9) <0.001

Number, median (IQR) 1.5 (1.0–2.0) 0.0 (0.0–1.0) <0.001

Presence of specifier items

Number, median (IQR) 3.0 (2.0–3.0) 0.0 (0.0–1.0) <0.001

Abbreviations: MDD, Major Depressive Disorder; QIDS, Quick Inventory of Depressive Symptomatol-ogy; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; AD, antidepressant; FU, follow-up.a For P-value: t-tests were used for continuous variables; Chi-square analyses were used for dichotomous variables; Mann-Whitney U-tests were used for non-normal distributed variables. b QIDS score without overlapping specifier items. c Including: Social Phobia, Panic Disorder with Agoraphobia, Panic Disorder without Agoraphobia, Ago-raphobia, and Generalized Anxiety Disorder in the past 6 months at baseline.

60 | Chapter 3

Multinomial logistic regression with categories of side effects as outcome (reference= 0 side effects) showed that the anxious distress specifier predicted a higher frequency of side effects, with trend-significance (i.e. ≥4 side effects: OR=2.74, 95%CI=0.95–7.89, P=0.061; Table 4). In contrast, no effect of the specifier was found on the reporting of 1–3 side effects (OR=0.76, 95%CI=0.30–1.96, P=0.575). Interestingly, no effect of comorbid anxiety disorders was found on the reported frequency of side effects. When analyses were repeated for the continuous specifier and anxiety disorder indicators, no significant results were found for either the continuous specifier or the number of anxiety disorders (Table 4).

43.2% 21.3%

0%10%20%30%40%50%60%70%80%90%

100%

Yes NoAnxious distress specifier

Pres

ence

of M

ajor D

epre

ssive

Di

sord

er af

ter 2

year

s

A

25.3% 30.9%

33.7% 49.1%

41.0% 20.0%

0%10%20%30%40%50%60%70%80%90%

100%


0

1 - 3

≥ 4

Number of side effects

% A

cros

s num

ber o

f sid

e effe

cts ca

tego

ries

B *

**

43.2% 21.3%

0%10%20%30%40%50%60%70%80%90%

100%


Pres

ence

of M

ajor D

epre

ssive

Di

sord

er af

ter 2

year

s

A

25.3% 30.9%

33.7% 49.1%

41.0% 20.0%

0%10%20%30%40%50%60%70%80%90%

100%


0

1 - 3

≥ 4

Number of side effects

% A

cros

s num

ber o

f sid

e effe

cts ca

tego

ries

B *

**

Figure 1.

A) Presence of Major Depressive Disorder (MDD) after 2 years in persons with MDD on adequate antidepressant treatment with and without the anxious distress specifier (N=149). B) Number of side-effects in persons with MDD on adequate antidepressant treatment with and without the anxious distress specifier (N=138).Symbol: * Statistically significant at P<0.05, ** Statistically significant at P<0.01.


3

Tab

le 2

. Dep

ress

ion

seve

rity

(QID

S sc

ore

afte

r 1 y

ear a

nd 2

yea

rs) i

n pe

rson

s with

MD

D o

n ad

equa

te a

ntid

epre

ssan

t tre

atm

ent (

N=1

49).

QID

S sc

ore

afte

r 1 y

eara

QID

S sc

ore

afte

r 2

year

sa

Adj

ustm

ent

soci

odem

ogra

phic

sA

ddit

iona

l adj

ustm

ent

seve

rity

Adj

ustm

ent

soci

odem

ogra

phic

sA

ddit

iona

l adj

ustm

ent

seve

rity

Mod

elD

icho

tom

ous

indi

cato

rB

SEPb

BSE

PbB

SEPb

BSE

Pb

1Pr

esen

ce o

f anx

ious

di

stre

ss sp

ecifi

er

No

Ref.

Ref.

Ref.

Ref.

Yes

1.97

0.54

<0.0

011.9

00.

560.

001

1.75

0.45

<0.0

011.6

30.

470.

001

2A

ny c

urre

nt a

nxie

ty

diso

rder

cN

oRe

f.Re

f.Re

f.Re

f.

Yes

0.64

0.57

0.26

70.

490.

590.

408

0.73

0.49

0.13

80.

520.

510.

308

3Pr

esen

ce o

f anx

ious

di

stre

ss sp

ecifi

er

No

Ref.

Ref.

Ref.

Ref.

Yes

2.00

0.58

0.00

11.9

40.

600.

001

1.71

0.49

0.00

11.6

30.

490.

001

Any

cur

rent

anx

iety

di

sord

erc

No

Ref.

Ref.

Ref.

Ref.

Yes

-0.0

90.

580.

884

-0.13

0.60

0.82

90.

120.

500.

810

0.02

0.51

0.97

0

Mod

elCo

ntin

uous

indi

cato

r

1N

umbe

r of a

nxio

us d

istr

ess

spec

ifier

item

s0.

720.

17<0

.001

0.70

0.18

<0.0

010.

600.

15<0

.001

0.56

0.16

<0.0

01

2N

umbe

r of c

urre

nt a

nxie

ty

diso

rder

sc0.

410.

280.

143

0.31

0.30

0.29

80.

340.

240.

151

0.20

0.26

0.44

7

3N

umbe

r of a

nxio

us d

istr

ess

spec

ifier

item

s0.

790.

20<0

.001

0.78

0.20

<0.0

010.

650.

18<0

.001

0.64

0.18

<0.0

01

Num

ber o

f cur

rent

anx

iety

di

sord

ersc

-0.21

0.31

0.48

9-0

.280.

320.

384

-0.15

0.26

0.56

0-0

.280.

280.

319

Abb

revi

atio

ns: M

DD,

Maj

or D

epre

ssiv

e D

isor

der;

QID

S, Q

uick

Inve

ntor

y of

Dep

ress

ive

Sym

ptom

atol

ogy.

a Q

IDS

scor

e w

ithou

t ove

rlapp

ing

spec

ifier

item

s. b Ba

sed

on li

near

regr

essi

on a

naly

ses.

c Inc

ludi

ng: S

ocia

l Pho

bia,

Pan

ic D

isor

der w

ith A

gora

phob

ia, P

anic

Dis

orde

r with

out A

gora

phob

ia, A

gora

phob

ia, a

nd G

ener

aliz

ed A

nxie

ty D

isor

der i

n th

e pa

st 6

m

onth

s at b

asel

ine.

62 | Chapter 3

Table 3. Remission (absence of an MDD diagnosis after 2 years) in persons with MDD on adequate antidepressant treatment (N=149).

Absence of an MDD diagnosis after 2 years

Adjustment sociodemographics

Additional adjustment severity

Model Dichotomous indicator OR 95%CI Pa OR 95%CI Pa

1 Presence of anxious distress specifier

No Ref. Ref.

Yes 0.35 0.16–0.76 0.008 0.42 0.19–0.91 0.028

2 Any current anxiety disorderb

No Ref. Ref.

Yes 0.53 0.25–1.14 0.103 0.64 0.29–1.42 0.273

3 Presence of anxious distress specifier

No Ref. Ref.

Yes 0.39 0.17–0.88 0.023 0.44 0.19–1.00 0.0496

Any current anxiety disorderb

No Ref. Ref.

Yes 0.74 0.33–1.66 0.460 0.84 0.36–1.95 0.681

Model Continuous indicator

1 Number of anxious distress specifier items

0.67 0.52–0.87 0.002 0.70 0.54–0.91 0.009

2 Number of current anxiety disordersb

0.70 0.49–1.00 0.045 0.79 0.54–1.16 0.226

3 Number of anxious distress specifier items

0.69 0.52–0.93 0.015 0.70 0.52–0.94 0.018

Number of current anxiety disordersb

0.90 0.60–1.36 0.625 1.01 0.66–1.56 0.957

Abbreviations: MDD, Major Depressive Disorder.a Based on logistic regression analyses. b Including: Social Phobia, Panic Disorder with Agoraphobia, Panic Disorder without Agoraphobia, Agoraphobia, and Generalized Anxiety Disorder in the past 6 months at baseline.


3

Tab

le 4

. Num

ber o

f sid

e eff

ects

in p

erso

ns w

ith M

DD

on

adeq

uate

ant

idep

ress

ant t

reat

men

t (N

=138

).

Num

ber

of a

ntid

epre

ssan

t sid

e eff

ects

a

Adj

ustm

ent s

ocio

dem

ogra

phic

sA

ddit

iona

l adj

ustm

ent s

ever

ity

1–3

SEs

(ver

sus

no S

Es)

≥4 S

Es (v

ersu

s no

SEs

) 1–

3 SE

s (v

ersu

s no

SEs

)≥4

SEs

(ver

sus

no S

Es)

Mod

elD

icho

tom

ous

indi

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64 | Chapter 3

The results show that the anxious distress specifier predicted greater depression severity at both 1- and 2-year follow-up, lower remission rates at 2-year follow-up, and greater frequency of antidepressant side effects in the period from baseline to 2-year follow-up in patients with MDD on adequate antidepressant treatment. Since a recent publication indicated that anxiety symptoms are linked to suicidal ideation in patients with MDD [29], we additionally checked this association in post-hoc analyses using the Scale for Sui-cide Ideation [30] to measure the presence (yes/no) of suicidal thoughts. We found that MDD patients with anxious distress had more suicidal thoughts after two years when compared to those without anxious distress (Supplementary Table S1). The dichotomous specifier predicted suicidal thoughts after 2 years better than the current anxiety disorder indicator (OR=4.47, 95%CI=1.44–13.84, P=0.009 versus OR=0.94, 95%CI=0.34–2.61, P=0.903). This was also the case for the continuous specifier when compared to the continuous anx-iety disorder indicator (OR=1.71, 95%CI=1.18–2.47, P=0.005 versus OR=0.91, 95%CI=0.55–1.51, P=0.706) (Supplementary Table S1).


3

Discussion

This is the first study to examine whether the DSM-5 anxious distress specifier is pre-dictive of poor treatment outcomes and patient-reported antidepressant side effects in patients with MDD receiving adequate antidepressant treatment that was recently ini-tiated. The anxious distress specifier was common, with a prevalence of 59.1% in this patient group. The specifier predicted poorer treatment outcomes as reflected by greater depression severity at both 1- and 2-year follow-up and lower remission rates at 2-year follow-up in patients with MDD on adequate antidepressant treatment compared to the patients without the specifier. Furthermore, the anxious distress specifier was also pre-dictive of greater frequency of antidepressant side effects in the period from baseline to 2-year follow-up. Moreover, the specifier outperformed comorbid DSM-IV-based anxiety disorders as a longitudinal predictor of all treatment outcomes.

These findings, together with those of our previous work on the anxious distress specifier [18], suggest that the specifier captures a distinct and clinically valid con-struct. While our previous study tested the longitudinal validity of the specifier and validated it against comorbid DSM-IV-based anxiety disorders in a large cohort of depressed patients (N=1,080), this study examined the predictive ability of the specifier on treatment outcomes in a select group of depressed patients on recently initiated antidepressant treatment (N=149). The results of this study contribute to insight into the specifier’s ability to predict treatment outcomes and its treatment implications, beyond the validity of the specifier itself and in comparison to DSM-IV-based anxiety disorders on clinical course and outcomes. The specifier is longitudinally predictive for lower remission rates and greater depression severity over time remains, consistent with a poorer treatment response in this depressed subset. With regard to antidepres-sant side effects, it is interesting that the specifier is predictive for greater frequency of side effects (≥4). This may be the result of a greater responsiveness to changes in the body during antidepressant treatment in depressed patients with concurrent anxiety. Patients with a greater frequency of side effects may be less compliant to antidepres-sant treatment which may have a detrimental effect on the chronicity or recurrence of their illness. A possible explanation for these findings might be a differential neurobi-ological profile underlying anxious depression [15]. A review by Ionescu and colleagues suggests that anxious depression is associated with distinct neurobiological findings when compared to non-anxious depression, for example regarding neuroimaging, the hypothalamic-pituitary-adrenal (HPA)-axis and genetics [15]. One study found that the BDNF rs7124442 TT genotype predicted a worse antidepressant response after 6 weeks in persons with anxious depression [15,31]. Results of several studies suggest a dysfunction of the HPA-axis in subjects with anxious depression [32-34]. Camacho

66 | Chapter 3

hypothesized that anxious depression may be a chronic inflammatory phenomenon, since it shares common pathophysiological pathways with inflammatory states [35]. Furthermore, the finding that the specifier is predictive of more suicidal thoughts after 2 years is in line with previous studies, as it has been shown that anxiety symptoms are linked to new-onset of suicidal ideation in patients with MDD [29] and suicidal ide-ation is associated with inadequate treatment response [36,37]. This suggest it may be extra clinically relevant to assess and evaluate suicidal thoughts in depressed patients meeting criteria of the anxious distress specifier. However, it should be noted that the 95%CIs are quite large which is likely due to the small number of patients reporting suicidal thoughts in the group without the specifier.

Thus, since the specifier seems to pick up patients who have poor treatment respon-siveness and a greater frequency of side effects, it may be clinically useful to assess the presence of anxious distress by means of the specifier in MDD patients for treatment planning and monitoring. Patients with depression and a comorbid anxiety disorder are likely to be patients requiring use of both antidepressant medication and psychotherapy [38], where psychotherapy may need to focus not only on depression, but also on anxiety and avoidance behaviours. To further optimize treatment strategies for patients with depression meeting criteria of the DSM-5 anxious distress specifier, it is also essential to determine the effectiveness and place of psychotherapy in their treatment plan. Further-more, the specifier may be an important factor to consider in clinical trials. Disentangling the potential differential neurobiological profile of the anxious distress specifier may contribute to better treatments for this subtype of MDD [10,15].

The results of this study are consistent with much of the literature examining popula-tions with anxious depression [7-11], although previous studies (conducted before the introduction of DSM-5) did not define anxious depression by means of the DSM-5 anxious distress specifier. For example, the Sequenced Treatment Alternatives to Relieve Depres-sion (STAR*D) study, which is the largest study that investigated treatment outcomes in an anxious depressed subsample, found that anxious depression was associated with poorer treatment responses and significantly greater ratings of side effects [8]. In addition, a Chinese study [9] found similar results: significantly lower remission rates and higher adverse event frequency rates in patients with anxious depression when compared to patients with non-anxious depression. Both studies defined anxious depression by means of a Hamilton Rating Scale for Depression anxiety/ somatization factor score. Therefore these studies, together with other previous studies conducted on anxious depression, do not contribute to determining the predictive value of the DSM-5 anxious distress specifier on treatment outcomes. The use of the specifier may have particular value in non-psychiatric settings, where busy general practitioners are often the first contact for


3

patients with depressive symptoms. Use of the specifier in these settings may provide useful information in predicting severity, outcomes, and side effects, allowing the clini-cian to adjust treatment approaches accordingly and to provide additional information to patients on expected side effects.

Our study is the first to examine treatment outcomes in a depressed population with versus without the DSM-5 anxious distress specifier. Our study used a 2 year follow-up period, while those of clinical trials are usually much shorter. For example, the large STAR*D study had a follow-up duration of 14–28 weeks. We examined the anxious distress specifier in a generalizable group of persons with MDD treated in standard clinical settings who recently started antidepressant treatment, for which dose and duration were optimal and in whom we could subsequently evaluate treatment out-comes. We used data from patients with MDD assessed according to DSM-IV diagnoses. Several limitations should be noted when interpreting the results. The specifier used for this study was constructed by self-reported proxy items instead of clinician-based assessments [18]. In addition, our proxy item regarding concentration is somewhat different than the DSM-5 criterion because difficulties with concentration as a result of depression may be different than those resulting from anxiety. However, results from our previous study demonstrated that our specifier reflected a valid conceptual assessment for anxious depression with significant discriminant performance and con-vergent and predictive validity [18]. In addition, while antidepressant medication use was registered by inspection of prescription drug containers brought in by patients, and confirmed by patient self-report, no additional confirmation from the prescribers was available for the small group of patients who did not bring their drug containers and for whom we relied on self-reports. However, the results of our analyses were not different if we excluded this subgroup from analyses. Since presence of any phobia is higher in the group of MDD with than without anxious distress, and phobia may be more refractory to antidepressant treatment, it could be possible that presence of any phobia affects the effects of the anxious distress specifier on treatment outcomes. However, we did evaluate whether adjustment for the presence of any phobia changed the results, and this showed that phobia is not an independent predictor, nor is it a factor that explains the observed effect of the anxious distress specifier for all treat-ment outcomes. Furthermore, the study design used was not an experimental trial but a naturalistic longitudinal cohort study.

In conclusion, this study shows that the DSM-5 anxious distress specifier is predictive for differential treatment response, greater chronicity and severity over time, and greater fre-quency of side effects. Therefore, this simple 5-item specifier is of potential great clinical usefulness for treatment planning and monitoring in depressed patients. Future research

68 | Chapter 3

should investigate its usefulness in differential treatment response in clinical trials. More-over, future research is needed to examine why anxious distress is associated with poorer treatment outcomes and whether this may reflect a differential underlying biological profile, thereby uncovering potential targets to optimize and enhance treatments for depressed patients with anxious distress.


3

References

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8 Fava M, Rush AJ, Alpert JE, Balasubramani GK, Wisniewski SR, Carmin CN, Biggs MM, Zisook S, Leuchter A, Howland R, Warden D, Trivedi MH: Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry 2008; 165:342-51.

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18 Gaspersz R, Lamers F, Kent JM, Beekman AT, Smit JH, van Hemert AM, Schoevers RA, Penninx BW: Longitudinal predictive validity of the DSM-5 anxious distress specifier for clinical outcomes in a large cohort of patients with major depressive disorder. J Clin Psychiatry 2016;-doi: 10.4088/JCP.15m10221.

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26 Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K: The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 1987; 334:1-100.

27 Uher R, Farmer A, Henigsberg N, Rietschel M, Mors O, Maier W, Kozel D, Hauser J, Souery D, Placentino A, Strohmaier J, Perroud N, Zobel A, Rajewska-Rager A, Dernovsek MZ, Larsen ER, Kalember P, Giovan-nini C, Barreto M, McGuffin P: Adverse reactions to antidepressants. Br J Psychiatry 2009; 195:202-10.

28 Bet PM, Hugtenburg JG, Penninx BWJH, Hoogendijk WJG: Side effects of antidepressants during long-term use in a naturalistic setting. Eur Neuropsychopharmacol 2013; 23:1443-51.

29 Baek JH, Heo JY, Fava M, Mischoulon D, Nierenberg A, Hong JP, Roh S, Jeon HJ: Anxiety symptoms are linked to new-onset suicidal ideation after six months of follow-up in outpatients with major depressive disorder. J Affect Disord 2015; 187:183-7.

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31 Domschke K, Lawford B, Laje G, Berger K, Young R, Morris P, Deckert J, Arolt V, McMahon FJ, Baune BT: Brain-derived neurotrophic factor ( BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol 2010; 13:93-101.

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3

Supplementary Material

Supplementary Table S1. Suicidal thoughts after 2 years in persons with MDD on adequate antide-pressant treatment (N=149).

Suicidal thoughts after 2 years

Additional adjustment severity and baseline suicidal thoughts

Model Dichotomous indicator OR 95%CI Pa

1 Presence of anxious distress specifier No Ref.

Yes 4.38 1.48–12.95 0.007

2 Any current anxiety disorderb No Ref.

Yes 1.42 0.55–3.68 0.466

3 Presence of anxious distress specifier No Ref.

Yes 4.47 1.44–13.84 0.009

Any current anxiety disorderb No Ref.

Yes 0.94 0.34–2.61 0.903

Model Continuous indicator

1 Number of anxious distress specifier items 1.65 1.19–2.30 0.003

2 Number of current anxiety disordersb 1.28 0.83–1.99 0.269

3 Number of anxious distress specifier items 1.71 1.18–2.47 0.005

Number of current anxiety disordersb 0.91 0.55–1.51 0.706

Abbreviations: MDD, Major Depressive Disorder.a Based on logistic regression analysis. b Including: Social Phobia, Panic Disorder with Agoraphobia, Panic Disorder without Agoraphobia, Agoraphobia, and Generalized Anxiety Disorder in the past 6 months at baseline.

72 | Chapter 3

Persons with MDD N=1,115

Complete data to construct specifier

N=1,090

AD use Baseline to 2yr FU

N=581

Recent start of AD treatment

N=230

Long-term AD users N=351

Treatment response analyses

N=149

Missing FU data N=19

Adequate AD treatment

N=168

No adequate AD N=62

No AD use Baseline to 2yr FU

N=509

Incomplete data to construct specifier

N=25

Supplementary Figure S1. Flowchart of sample selection to include patients with MDD on adequate antidepressant treatment.

Abbreviations: MDD, Major Depressive Disorder; AD, antidepressant; FU, follow-up.

anxious distress predicts subsequent 3.pdf · 52 | chapter 3 abstract introduction: evidence has...

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