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The differential influence of life stress on individual symptoms of depression

Fried EI, Nesse RM, Guille C, Sen S. The differential influence of life stress on individual symptoms of depression.

Objective: Life stress consistently increases the incidence of major depression. Recent evidence has shown that individual symptoms of major depressive disorder (MDD) differ in important dimensions such as their genetic and etiological background, but the impact of stress on individual MDD symptoms is not known. Here, we assess whether stress affects depression symptoms differentially. Method: We used the chronic stress of medical internship to examine changes of the nine Diagnostic and Statistical Manual (DSM)-5 criterion symptoms for depression in 3021 interns assessed prior to and throughout internship. Results: All nine depression symptoms increased in response to stress (all P < 0.001), on average by 173%. Symptom increases differed substantially from each other (P < 0.001), with psychomotor problems (289%) and interest loss (217%) showing the largest increases, and suicidal ideation (146%) and sleep problems (52%) the smallest. Symptoms also differed in their severities under stress (P < 0.001): Fatigue, appetite problems and sleep problems were most prevalent; psychomotor problems and suicidal ideation were least prevalent. Conclusion: Stress differentially affects the DSM-5 depressive symptoms. Analyses of individual symptoms reveal important insights obfuscated by sum-scores.

E. I. Fried1, R. M. Nesse2, C. Guille3, S. Sen4 1Faculty of Psychology and Educational Sciences, University of Leuven, Leuven, Belgium, 2School of Life Sciences, Arizona State University, Tempe, AZ, 3Medical University of South Carolina, Charleston, SC and 4Department of Psychiatry, Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI, USA

Key words: depressive symptoms; major depressive disorder; life stress; internship

Dr Srijan Sen, Rachel Upjohn Building, 4250 Plymouth Rd, Ann Arbor, MI 48109-5734, USA. E-mail: [email protected]

Accepted for publication January 8, 2015

Significant outcomes

• While all MDD symptoms increase in response to internship stress, symptoms differ dramatically in magnitude of increases.

• MDD symptoms show pronounced prevalence differences under stress.

Limitations

• Internship stress is a particular stressor in a fairly homogeneous population, and extrapolation to the general population and other stressors should be performed with caution.

• This study did not assess the direction of depressive symptoms with complex natures (e.g. hypersom- nia vs. insomnia).

Introduction

Major depressive disorder (MDD) is a highly het- erogeneous disorder (1–3). The Diagnostic and Statistical Manual (DSM-5) (4) uses nine symp- toms to define depression, three of which are com- prised of opposite symptoms (e.g. ‘insomnia or hypersomnia’), leading to 1497 unique symptom

profiles that qualify for the same diagnosis (5). In line the with the National Institute for Mental Health (NIMH) strategic plan for mood disorder research (6), a growing body of evidence suggests that the analysis of individual depression symp- toms is an untapped source of important and clini- cally relevant data. For instance, MDD symptoms differ from each other in their genetic (7–9) and

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etiological (10) background, differentially impact impairment of psychosocial functioning (11) and show differential associations with important clini- cal variables such as demographic information, personality traits, life events and lifetime comor- bidities (12).

Life stress is one of the most robust triggers for MDD (13,14). Elevated levels of depression after experiencing stress have been documented both in patients and general population samples (14,15), with depression rates 2.5–7 times higher for indi- viduals exposed to serious stressors (16,17). Despite the overwhelming evidence that depression diagnoses are increased in the context of stress, we know little about the behaviour of individual depressive symptoms in response to stress.

Here, we prospectively investigate the impact of life stress on the nine DSM MDD criterion symp- toms in a cohort study of interns. Internship is a well-established serious chronic stressor, and interns are faced with long work hours, sleep depri- vation, loss of autonomy, as well as extreme emo- tional situations (18,19). In a previous longitudinal study of interns, depression levels increased from 3.9% at baseline to 25.7% during internship (20). Utilizing internship as prospective stress model offers the opportunity to assess depression symp- toms in a large sample before and after the reliable onset of severe chronic stress.

Aims of the study

The present report uses a cohort of 3021 interns to examine whether internship stress impacts some depression symptoms more strongly than others, as well as the magnitude of potential differences.

Material and methods

Sample

Seven thousand and four hundred and twenty-nine interns entering internship programmes in the USA during the 2007–2012 academic years were invited to participate in the study; 59% (N = 4383) accepted the invitation. The institutional review boards at participating hospitals approved the study. Partici- pating subjects provided electronic informed consent and were given $50 in gift certificates.

Assessment

All surveys were conducted through a secure online Web site designed to maintain confidential- ity. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9) (21). The

PHQ-9 is a self-report component of the PRIME- MD inventory that screens for the DSM-5 crite- rion symptoms of depression. For each of the nine symptoms, subjects indicated whether, during the previous 2 weeks, the symptom had bothered them ‘not at all’, ‘several days’, ‘more than half the days’ or ‘nearly every day’. Each item yields a score of 0, 1, 2 or 3. The nine symptoms assessed by the PHQ- 9 are as follows: ‘little interest or pleasure in doing things’ (interest), ‘feeling depressed or hopeless’ (mood), ‘sleep problems’ (sleep), ‘feeling tired’ (fatigue), ‘appetite problems’ (appetite), ‘feeling bad about yourself/that you are a failure’ (self- blame), ‘trouble concentrating on things’ (concen- tration), ‘moving or speaking slowly/being fidgety or restless’ (psychomotor) and ‘suicidal ideation’ (suicide).

Subjects completed a baseline survey 1– 2 months prior to commencing internship that assessed general demographic factors (age, sex) and depressive symptoms (PHQ-9). Participants were contacted via email 3, 6, 9 and 12 months into their internship year and asked to complete the PHQ-9 again.

Statistical analysis

We compared symptom severity at baseline with average symptom severity during the four mea- surements across the internship. This approach has been used in previous publications based on this dataset (10,20) and has the advantage of increased reliability of symptom assessment within intern- ship through repeated measurement. When averag- ing the within-internship symptom scores, 1362 (31.1%) of the 4383 subjects were dropped via list- wise deletion because they had missing data on two or more time points, leaving 3021 interns in the analytic sample.

Overall, three analyses were performed. First, we investigated whether PHQ-9 symptoms increased with stress. We used one paired samples t-test per symptom to compare severities and adjusted P-values for multiple testing using the Bonferroni correction.

Second, we tested whether symptoms differed from each other in response to stress, a test to assess whether stress had differential impacts on specific depressive symptoms. Instead of perform- ing 36 individual tests comparing each symptom increase against all other symptom increases, we conducted one omnibus test. We fitted two longitu- dinal mixed models to the data with the subject variable as a random effect, using the LMER func- tion of the R-package LME4 (22). In model I, symp- tom increases from baseline to the stress condition

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were allowed to be freely estimated, whereas increases were constrained to be equal in model II (i.e. slopes were forced to be equal). We then exam- ined whether the constrained model II showed sig- nificantly decreased model fit compared with model I, as would be expected if symptoms increased differentially in response to stress. We compared models using a chi-squared difference test and used the Bayesian information criterion (BIC) (23) as goodness-of-fit statistic (the lower the value, the better the fit).

Third, we examined the stress condition symp- tom score to see whether the nine depressive symp- toms differed in their severities after stress onset. Similar to analysis two, we performed one omni- bus test by fitting two mixed models to the cross- sectional data of timepoint two using the LMER function of the R-package LME4, once again using the subject variable as random effect. Model I allowed for a free estimation of symptom severi- ties, while model II constrained all symptoms to have equal severities. Model fit was compared sim- ilar to analysis two.

Lastly, we provide detailed descriptive informa- tion about symptom severity and increases. Analy- sis one was performed using SPSS v21.0 (24) and analyses two and three with R v3.1.0 (25). We con- sider P-values of <0.05 significant.

Results

Sample characteristics

Three thousand and twenty-one individuals were included in the analyses; 48.4% of the study partic- ipants were males, and the mean age was 27.5 (SD = 2.7) (Table 1). Participants that were dropped due to missing values did not differ signifi- cantly from the retained participants regarding the variables age, sex or history of depression (all P > 0.05).

Symptom increases

All symptoms increased significantly over time (t- values between 12.3 and 57.6, all P < 0.001) (Table 2) (Fig. 1). Symptoms increased by an aver- age of 173.4%, ranging from 51.5% (sleep) to 289.2% (psychomotor) (Fig. 2).

Symptoms differed in their increases: Model I (variable symptom increases across time) fits the data significantly better than model II (equal symptom increases across time) (v2diff = 2652, dfdiff = 8, P < 0.001) (Table 3). This means that stress had differential impact on the nine depres- sive symptoms.

Symptoms under stress

Model I (variable symptom severities under stress) showed a superior fit compared with model II (equal symptom severities under stress) (v2diff = 13 644, dfdiff = 8, P < 0.001) (Table 3). The three symptoms fatigue (Mean = 1.40), appetite (M = 0.93) and sleep (M = 0.82) showed the highest mean severity under stress, while the two symptoms, suicide (M = 0.10) and psycho- motor (M = 0.23), showed the lowest mean severity.

Discussion

The present study examined the impact of chronic stress on the nine DSM-5 criterion symptoms for depression by prospectively assessing a population

Table 1. Demographic characteristics of study participants

Variable Number (%)

Sex Male 1462 (48.4) Female 1559 (52.6)

Age, years ≤25 536 (17.7) 26–30 2146 (71) 31–35 281 (9.3) >35 58 (<0.1)

History of depression Yes 1326 (43.9) No 1693 (55.1)

Specialty Internal medicine 1106 (36.6) Other 394 (13) Pediatrics 350 (11.6) General surgery 306 (10.1) Psychiatry 217 (7.2) Emergency medicine 197 (6.5) Family medicine 137 (4.5) Obstetrics/gynecology 123 (4.1) Internal medicine/pediatrics 73 (2.4) Neurology 48 (1.6) Transitional 43 (1.4) Missing 27 (0.9)

Table 2. Symptom severities and increases

n = 3021

Baseline Under stress Increases

Mean SD Mean SD % P

Interest 0.21 0.48 0.66 0.57 216.5 < 0.001 Mood 0.24 0.48 0.64 0.59 168.3 < 0.001 Sleep 0.54 0.73 0.82 0.71 51.5 < 0.001 Fatigue 0.57 0.69 1.40 0.70 145.4 < 0.001 Appetite 0.35 0.64 0.93 0.77 164.4 < 0.001 Self-blame 0.21 0.50 0.58 0.64 175.0 < 0.001 Concentration 0.17 0.47 0.52 0.62 204.4 < 0.001 Psychomotor 0.06 0.29 0.23 0.42 289.2 < 0.001 Suicide 0.04 0.21 0.10 0.27 146.0 < 0.001

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of 3021 individuals before and after the onset of medical internship. While all symptoms increased during internship, the impact of stress varied dra- matically across symptoms, with some symptoms increasing substantially more than others; espe- cially, psychomotor problems, loss of interest and concentration problems exhibited pronounced increases. The somatic symptoms fatigue, appetite and sleep problems were most prevalent under stress.

Prior studies have focused on the relationship between stress and depression subtypes, but no clear pattern has emerged (26–28). This inconsis- tency is likely due to problems pertaining to the validity of MDD subtypes (29,30), a reliance on retrospective self-report of life stress that can be substantially biased (31,32), and a cross-sectional design that confounds the bidirectional influences of life stress and depression (14). The current study addresses these limitations, with a prospective

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design that allows for a causal interpretation: Stress leads to substantial and heterogeneous increases of depressive symptoms.

Implications

The present report documents substantial variabil- ity in symptom change across time and symptom severity under stress. This work adds to a growing body of evidence illuminating important differ- ences between individual symptoms of depression (7,10,33) and indicates that the reliance on sum- scores and thresholds obfuscates crucial informa- tion about the nature of depressive symptoms. This covert heterogeneity may help to explain recent ‘disappointing’ findings such as low reliability for MDD diagnoses in the DSM-5 field trials (34), low antidepressant efficacy compared with placebo response (35), lack of common genetic markers associated with antidepressant response (36) and failure to detect even small genetic effects with depression diagnosis in large genomewide associa- tion studies (37).

The investigation of individual symptoms reveals clinically useful insights. For instance, about 72% of the interns in our study reported sleep problems on at least several days per week under stress. Sleep problems are a well-established predictor for the development of future episodes of depression (38), decrease treatment efficacy (39,40), and directly targeting sleep problems in depressed patients may increase overall depression improvement (41,42). We believe that utilizing symptom information is a crucial step toward the development of more efficient prevention and intervention strategies and may help us understand underlying biological processes better than diagno- sis level analyses.

The DSM criterion symptoms assessed in this study are only a small subset of potential MDD

symptoms (43) and were largely determined by clinical consensus instead of empirical evidence (12). Various other symptoms, including anxiety, irritability and anger, are prevalent among individ- uals diagnosed with MDD and may have great value in predicting the course of the disease (44,45). Assessing symptoms outside of traditional DSM criteria could advance future studies of stress and depression as well as treatment of patients, and is in line with the National Institute of Mental Health finding that strictly adhering to DSM diag- nostic criteria may be inhibiting progress in eluci- dating the biological roots of mental illness (46). A recent study also documented that specific dimen- sions of rating scales for depression, such as the 6- item melancholia subscale of the 17-item Hamilton Rating Scale for Depression (HAM-D17) (47,48), are more sensitive to treatment response than large multidimensional scales (49). The authors con- cluded that such subscales may possess greater bio- logical validity and thus circumvent problems of heterogeneity inherent to most depression rating scales.

Limitations

The present report has three limitations. First, we only investigated symptom change in response to one specific stressor. While the par- ticular pattern of symptom change is likely to be different with different stressors, the results of this study and others (50–52) suggest that it is unlikely that other stressors will uniformly increase the prevalence of all depressive symp- toms equally. Second, interns are not a represen- tative sample, so extrapolation to the general population should be performed with caution. Third, the PHQ-9 neither assesses the direction of depressive symptoms with complex natures (e.g. hypersomnia or insomnia instead of sleep problems) nor MDD symptoms outside of the DSM-5 criteria.

Acknowledgements

We thank M. Schultze and Dr K. Shedden for their valuable statistical input and all interns who participated in the study for their kind cooperation. The research leading to the results reported in this paper was sponsored in part by the Cluster of Excellence ‘Languages of Emotion’ (Grant no. EXC302) as well as the Research Foundation Flanders (Grant no. G.0806.13). Funding was also provided by the NIMH (R01 MH101459, K23 MH095109).

Declarations of interest

All authors declare that they have no conflict of interests.

Table 3. Chi-squared difference tests for the two model comparisons

df BIC v2diff dfdiff P

Differential symptom change Model I† 20 275 106 Model II‡ 12 277 680 2662 8 <0.001

Differential symptom severity Model I§ 11 137 110 Model II¶ 3 150 530 13 502 8 <0.001

df, degrees of freedom; BIC, Bayesian information criterion; v2diff , chi-squared statis- tic of the chi-squared difference test; dfdiff, degrees of freedom of the chi-squared difference test; P, P-value of the chi-squared difference test. †Variable symptom increases across time. ‡Equal symptom increases across time. §Variable symptom severities after stress onset. ¶Equal symptom severities after stress onset.

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