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. Author manuscript; available in PMC: 2022 Dec 20.
Published in final edited form as: J Affect Disord. 2020 Jun 26;275:44–47. doi: 10.1016/j.jad.2020.06.021

Improvements in Irritability with Sertraline Versus Placebo: Findings from the EMBARC Study

Manish K Jha 1,2, Abu Minhajuddin 1, Cherise Chin Fatt 1, Madhukar H Trivedi 1
PMCID: PMC9764261  NIHMSID: NIHMS1608179  PMID: 32658822

Abstract

Background:

This report seeks to evaluate improvements in symptoms of irritability with sertraline (a selective serotonin reuptake inhibitor antidepressant) versus placebo.

Methods:

Participants of Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study who were randomized to 8 weeks of treatment with either sertraline or placebo and completed 5-item irritability domain of Concise Associated Symptom Tracking scale (CASTIRR) at baseline were included (n=292). Repeated measures mixed model analysis with CAST-IRR as the outcome variable and treatment arm-by-time interaction as the independent variable of interest evaluated whether changes in irritability with treatment differed between sertraline and placebo arms. A separate analysis controlled for levels of overall depression severity (17-item Hamilton Depression Rating Scale). Covariates included age, sex, race, ethnicity, and site.

Results:

There was a significant treatment arm-by-time interaction (F = 6.96, df = 6, 1418, p <0.0001) suggesting that changes in irritability with sertraline differed from placebo. The magnitude of reduction in irritability from baseline to week-8 was greater with sertraline than with placebo (Cohen’s d effect size = 0.56). After controlling for levels of overall depression severity at each visit, reduction in irritability with time continued to be significant with sertraline but not with placebo.

Limitations:

Secondary analysis, limited generalizability, lack of non-serotonergic antidepressants.

Discussion:

There is greater improvement in irritability with sertraline than with placebo. Improvement in irritability with sertraline was independent of its effects on overall depression severity.

Keywords: Irritability, major depressive disorder, antidepressant, SSRI, placebo, randomized controlled trial

1. Introduction

Over half of adults with major depressive disorder (MDD) report significant irritability (Fava et al., 2010). Yet, it remains understudied, is not included as a criterion symptom of MDD in adults, and is not assessed by commonly used measures of overall depression (Eshel and Leibenluft, 2019; Kroenke et al., 2001). The 5-item irritability domain of Concise Associated Symptom Tracking scale (CAST-IRR) is an easy-to-administer and valid self-report measure of irritability (Jha et al., 2018; Minhajuddin et al., 2020; Trivedi et al., 2011). A recent report demonstrated the clinical utility of CAST-IRR by showing that early (baseline-to-week-4) changes in CAST-IRR with antidepressant treatment were independent of changes in overall depression (Jha et al., 2019b). Furthermore, early changes in irritability can be combined with changes in overall depression to reliably predict longer-term clinical outcomes (Jha et al., 2019b; Minhajuddin et al., 2020). However, these previous reports have been limited by absence of a placebo arm to demonstrate whether improvement in irritability is specific to antidepressant medication(s).

Greater reductions in irritability with selective serotonin reuptake inhibitors (SSRIs) versus placebo has been reported in various psychiatric conditions. In premenstrual dysphoric disorder, use of sertraline (an SSRI antidepressant) was associated with significantly greater reduction in irritability symptoms than with placebo (Yonkers et al., 1997). Similarly, use of sertraline was associated with lower irritability versus placebo in smokers with a history of depression who were undergoing smoking cessation (Covey et al., 2002). Use of citalopram, another SSRI antidepressant, was associated with greater reduction in irritability in elderly patients with dementia and emotional disturbances (Gottfries et al., 1992) as well as in youths with severe mood dysregulation (Towbin et al., 2019). However, to our knowledge, no previous study has evaluated the effect of SSRI antidepressants over placebo in reducing irritability among adult outpatients with MDD. Furthermore, previous studies did not control for changes in overall depression when evaluating SSRI vs. placebo differences in reduction of irritability.

This report, based on an unplanned secondary analysis of data from Stage 1 of Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study (Trivedi et al., 2016), evaluated whether treatment with sertraline is associated with greater reduction in irritability versus placebo. Specific questions included:

  1. Is there greater reduction in irritability with sertraline versus placebo?

  2. If yes, is this accounted for by changes in overall depression?

2. Methods

2.1. Study design and participants

The modified intent to treat sample for this secondary analysis of EMBARC (NCT01407094) study included participants with MDD who were in a current episode of at least moderately severe depression (at both screening and randomization visits), did not meet criteria for any failed antidepressant trial in the current episode [based on Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (Chandler et al., 2010)], were randomized either to sertraline or placebo, and completed CAST-IRR at baseline (n=292). As previously described, the EMBARC study (Trivedi et al., 2016; Trivedi et al., 2018) enrolled 309 participants at four sites after obtaining approval from the Institutional Review Board at site, and documenting written informed consent from each individual participant. Of these 309 participants, 10 were in a feasibility sample, 3 were randomized but not eligible for study, and 4 did not complete CAST-IRR at baseline. The eligibility criteria of EMBARC study have been described previously. Briefly, participants were 18–65 years of age, agreed to and were eligible for all biomarker procedures (electroencephalography, psychological testing, magnetic resonance imaging, and blood draws), and were excluded if they did not tolerate sertraline or bupropion in the past, were pregnant/breastfeeding/planning to become pregnant, were medically or psychiatrically unstable, met criteria for psychotic/bipolar disorder in lifetime or substance abuse in past 2 months or substance dependence in past 6 months, or were on prohibited concomitant medications (antipsychotic, anticonvulsant, mood stabilizers, central nervous system stimulants, daily use of benzodiazepines or hypnotics, or antidepressants).

2.2. Measurements

2.2.1. Hamilton Depression Rating Scale (HAMD-17)

Clinicians conducted the structured interview for HAMD-17 to assess overall depression severity at each visit of the EMBARC study. Individual items have 3–5 choices which are scored from 0–2 or 0–4 (Hamilton, 1960). Sum of scores of individual items can indicate depression severity of none (<6), mild (6–13), moderate (14–18), severe (19–23) and very severe (>24). Previous reports have found high concurrent validity of HAMD-17 with other measures of depression severity (Vittengl et al., 2005).

2.2.2. Concise Associated Symptom Tracking scale irritability domain (CAST-IRR)

The 5 items of this self-report measure assess symptoms of irritability (“I wish people would just leave me alone”, “I feel very uptight”, “I find myself saying or doing things without thinking”, “Lately everything seems to be annoying me” and “I find people get on my nerves easily”) where each individual item is rated on a 5-point Likert scale with responses of “strongly disagree”, “disagree”, “neither agree nor disagree”, “agree”, and “strongly agree” corresponding to scores of 1, 2, 3, 4, and 5 respectively and a total score of 5–25. In previous reports, Cronbach’s α of CAST-IRR was 0.77–0.83 (Jha et al., 2018; Minhajuddin et al., 2020).

2.3. Treatment arms

Participants were randomized to treatment with either sertraline or placebo for 8 weeks in a double-blind fashion (both participants and study team) in 1:1 ratio after stratification by site. Dose adjustments were made using the principles of measurement-based care by evaluating depression severity, side-effects, and adherence (Trivedi et al., 2006). Sertraline was started at 50 mg and placebo was started with a single pill. Dose changes were made in 50 mg or 1 pill increments on a weekly basis.

2.4. Statistical analysis plan

As reported earlier, the modified intent to treat sample of this report included all EMBARC study participants who were randomized to sertraline or placebo and completed CAST-IRR at baseline (n=292). Descriptive statistics were used for selected baseline clinical and sociodemographic factors. Baseline-to-week-8 reduction in CAST-IRR was computed in those with data available to compute effect size. A repeated-measures mixed model analysis with CAST-IRR as the dependent variable and treatment arm-by-visit interaction as the independent variable of interest was used to assess if rate of change in CAST-IRR over 8 weeks of treatment differed between sertraline and placebo. To evaluate if these changes were independent of changes in overall depression, the mixed model analysis was repeated after controlling for HAMD-17 at each visit. Contrasts for treatment arm-by visit interaction from these models were used to compare changes with treatment. Age, sex, race, ethnicity and site were used as covariates in all mixed model analyses. In exploratory analysis, a treatment arm-by-baseline CAST-IRR-by-time interaction in repeated measured mixed model analyses with HAMD_17 as the dependent variable evaluated whether baseline severity of irritability differentially predicted improvement in overall depression with sertraline versus placebo, i.e., moderated the antidepressant effect of sertraline. All analyses were conducted using SAS 9.4 and threshold of significance was set at p <0.05.

3. Results

At baseline, levels of irritability in participants randomized to sertraline [n=143, mean = 16.7, standard deviation (SD) = 4.08] and placebo (n=149, mean = 16.0, SD = 3.82) were similar. The two treatment arms were also similar on selected baseline clinical and sociodemographic variables (Table 1).

Table 1.

Baseline sociodemographic characteristics of EMBARC study participants with MDD and CASTIRR available at baseline (n=292).

Sertraline (n=143) Placebo (n=149)
Categorical variables N % N %
Sex
Male 43 43.0 57 57.0
Female 100 52.1 92 47.9
Race
White 87 46.0 102 54.0
Black 33 56.9 25 43.1
Other 23 51.1 22 48.9
Site
New York 43 49.4 44 50.6
Boston 23 46.8 26 53.1
Michigan 28 48.3 30 51.7
Texas 49 50.0 49 50.0
Hispanic ethnicity 29 52.7 26 47.3
Employed at baseline* 77 48.4 82 51.6
Continuous variables Mean SD Mean SD
Age in years 36.9 13.73 37.0 12.85
Years of education 15.0 2.61 15.2 2.63
HAMD-17 18.4 4.48 18.7 4.27
QIDS-SR 18.4 2.78 17.8 2.71
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*

missing n=4. EMBARC is Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care study, CAST-IRR is 5-item irritability domain of Concise Associated Symptom Tracking scale, HAMD-17 is 17-item Hamilton Depression Rating Scale, and QIDS-SR is 16-item Quick Inventory of Depressive Symptomatology Self-Report version.

3.1. Is there greater reduction in irritability with sertraline versus placebo?

Yes.

There was a significant treatment arm-by-visit interaction (F = 6.96, df = 6, 1418, p <0.0001) in mixed model analyses with CAST-IRR as the dependent variable, see Supplementary Table 1 for details. As shown in Figure 1, levels of CAST-IRR were significantly lower at week-4 (p = 0.003), week-6 (p = 0.025) and week-8 (p = 0.0004) in sertraline arm than in placebo arm. The magnitude of reduction in irritability from baseline to week-8 was greater (Cohen’s d effect size = 0.56) with sertraline (n = 108, mean = −4.4, SD = 4.33) than with placebo (n = 124, mean = −1.8, SD = 4.78).

Figure 1.

Figure 1.

Open in a new tab

Changes in irritability during Stage 1 of EMBARC study

Least square (LS) means obtained from mixed model analyses (error bars present standard errors) with 5-item irritability domain of Concise Associated Symptom Tracking (CAST-IRR) as the dependent variable in the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. Participants were randomized in 1:1 fashion to sertraline (n=143) or placebo (n=149) for 8 weeks during Stage 1 of EMBARC. * p <0.05 for sertraline versus placebo comparison.

3.2. If yes, is this accounted for by changes in overall depression?

No.

Even after controlling for overall depression at each visit, the treatment arm-by-visit interaction was significant (F = 6.96, df = 6, 1406, p <0.0001) in mixed model analyses with CAST-IRR as the dependent variable, see Supplementary Table 1 for full details. After controlling for HAMD-17 at each visit, levels of CAST-IRR were significantly lower at week-2 (p = 0.022), week-3 (p = 0.030), week-4 (p = 0.010) and week-8 (p = 0.001) in sertraline arm than in placebo arm, see Supplementary Figure 1. Furthermore, there was no significant change in CAST-IRR with time in placebo arm [contrast between CAST-IRR at baseline and at week-8: estimate (β) = −0.06, standard error (SE) = 0.30, p = 0.84]. However, reduction in CAST-IRR in sertraline arm (contrast between CAST-IRR at baseline and at week-8: β = 2.26, SE = 0.32, p <0.0001) continued to be significant even after controlling for HAMD-17 at each visit.

3.3. Exploratory analysis

The three way treatment arm-by-baseline CAST-IRR-by-time interaction was not significant (F=0.81, df=6, 1470, p=0.56) suggesting that the effect of sertraline versus placebo on reduction HAMD-17 did not differ based on pre-treatment levels of CAST-IRR.

4. Discussion

In this large study of depressed outpatients, we found that use of sertraline was associated with greater reduction in irritability than placebo. Reduction in irritability with sertraline was significant even after controlling for overall depression. In contrast, in the placebo arm, the reduction in irritability was no longer significant after controlling for overall depression. Taken together, these findings suggest that antidepressants have a specific effect on improvement of irritability that is distinct from their effect on other symptoms of depression.

Findings of this report are consistent with previous reports of improved irritability with sertraline versus placebo for other psychiatric indications such as treatment of premenstrual dysphoric disorder and smoking cessation (Covey et al., 2002; Yonkers et al., 1997). Findings of this report that treatment with sertraline is associated with reduction in irritability even after controlling for overall depression is consistent with a previous report from Combining Medications to Enhance Depression Outcomes (CO-MED) trial (Jha et al., 2019b). However, unlike CO-MED trial where all treatment arms had a serotonergic antidepressant, comparison with placebo in the current report demonstrates that reduction in irritability is specific to sertraline (and potentially other serotonergic antidepressants such as SSRIs). Previous reports have also found greater improvements in constructs related to irritability, such as hostility and anger attacks (Jha et al., 2020), with SSRIs than with placebo (Fava, 1998).

Findings of this report may have direct clinical implications. As commonly used measures of overall depression severity do not fully capture the antidepressant-specific improvements in irritability, findings of this report argue for assessment of irritability as part of routine measurement-based clinical practice (Jha et al., 2019a). Furthermore, use of antidepressant medications may be considered in the presence of burdensome symptoms of irritability.

There are several limitations of this report. As findings of these report are based on an unplanned secondary analysis, they should be considered preliminary and require confirmation in other samples of patients with depression. Furthermore, lack of additional treatment arms limits the interpretation of these findings; whether they are specific to sertraline or extend to other SSRIs, serotonergic antidepressants from other classes (such as serotonin norepinephrine reuptake inhibitor or tricyclic antidepressants), or non-serotonergic antidepressants. The eligibility criteria for EMBARC study and recruitment of participants from academic medical centers restrict the generalizability of these findings to community samples.

5. Conclusions

Use of sertraline is associated with greater reduction in irritability than placebo in adult outpatients with MDD. These findings are not accounted for by reductions in overall depression. These findings argue for measurement of irritability in clinical practice and use of antidepressants for treatment of irritability.

Supplementary Material

1
2

Highlights.

  • Greater improvement in irritability with sertraline than with placebo.

  • Moderately large effect size favoring sertraline (Cohen’s d = 0.56).

  • Reduction in irritability with sertraline was independent of changes in depression.

Acknowledgements

The authors thank the investigators and clinical staff at each site for their assistance with this project; all of the study participants; and Georganna Carlock for administrative support.

Funding

The Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study was supported by NIMH grants U01MH092221 (PI: Trivedi) and U01MH092250 (PIs: McGrath, Parsey, and Weissman). This work was also funded in part by the Hersh Foundation (PI: Trivedi). The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NIMH had no role in the drafting or review of the manuscript or in the collection or analysis of the data.

Footnotes

Conflict of Interest Statement

Drs. Minhajuddin and Chin Fatt have no conflicts to report.

Dr. Jha has received contract research grants from Acadia Pharmaceuticals and Janssen Research & Development, and honoraria for CME presentations from North American Center for Continuing Medical Education and Global Medical Education.

Dr. Trivedi has served as an adviser or consultant for Abbott Laboratories, Abdi Ibrahim, Akzo (Organon Pharmaceuticals), Alkermes, AstraZeneca, Axon Advisors, Bristol-Myers Squibb, Cephalon, Cerecor, CME Institute of Physicians, Concert Pharmaceuticals, Eli Lilly, Evotec, Fabre Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Global Services, Janssen Pharmaceutica Products, Johnson & Johnson PRD, Libby, Lundbeck, Meade Johnson, MedAvante, Medtronic, Merck, Mitsubishi Tanabe Pharma Development America, Naurex, Neuronetics, Otsuka Pharmaceuticals, Pamlab, Parke-Davis Pharmaceuticals, Pfizer, PgxHealth, Phoenix Marketing Solutions, Rexahn Pharmaceuticals, Ridge Diagnostics, Roche Products, Sepracor, Shire Development, Sierra, SK Life and Science, Sunovion, Takeda, Tal Medical/Puretech Venture, Targacept, Transcept, VantagePoint, Vivus, and Wyeth-Ayerst Laboratories; he has received grants or research support from the Agency for Healthcare Research and Quality, Cyberonics, NARSAD, NIDA, and NIMH.

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Supplementary Materials

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NIHMS1608179-supplement-1.docx (226.5KB, docx)
2
NIHMS1608179-supplement-2.docx (22.3KB, docx)

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