Psychology Paper

Recent Australian statistical data [1,2] reported a 12-month prevalence of depression of 5.1% while an Australian textbook suggested that ‘10% of the popula- tion will have depressive illness’ and that 20% of patients attending general practitioners (GPs) are significantly depressed [3].

Several authors stress the under-diagnosis of depres- sion by GPs [4–6]. As GPs are the first medical doctors

to whom depressed patients turn for help, it was decided to improve their knowledge in diagnosis and treatment of this disorder. A program of several ‘Insights’ workshops was developed to be attended by participating GPs. These workshops were developed by an independent advisory committee of GPs and psychiatrists with the aim of refreshing and updating knowledge on depres- sion, its diagnosis and treatment, including nonpharma- cological, pharmacology and psychosocial interventions.

A baseline questionnaire was developed to be admin- istered at the beginning of the program.

This paper is based on the analysis of the pre- workshop data and provides information on the knowl- edge of depression reported by GPs prior to entering the ‘Insights’ program.

The identification and treatment of depression by General Practitioners

Jerzy Krupinski, John W.G. Tiller

Objective: To assess the level of recognition and knowledge about treatment of depres- sion by General Practitioners (GPs). Method: Analysis of questionnaires completed by participants commencing a series of workshops aimed at improving their knowledge of the diagnosis and treatment of depres- sion. Of the 3289 GPs involved in the program 2500 (76% respondent rate) completed the questionnaires in a group situation. There was no difference between respondents and non- respondents in terms of age, gender and year of graduation. Results: The majority of GPs believe they have a satisfactory competence in the recogni- tion and treatment of depression, although a sizeable minority based their diagnosis pre- dominantly on somatic symptoms. The GPs felt confident about their knowledge and skills in counselling and the use of antidepressant medication, but not in dealing with children and suicidal or pregnant patients. The most common symptoms used to identify ‘depression’ were sleep disorders and only 54% listed depressed mood as a symptom on which the diagnosis is based. Only 28% reported sufficient symptoms to meet criteria for DSM-IV major depressive disorder, which supports views that these criteria are inappropriate for general practice. Fifty-seven percent of doctors used medicine together with nonpharma- cological treatment in the majority of patients, and medications doses were almost all within the range recommended in the product information. Conclusions: There is a need to improve GPs knowledge in diagnosing depression, in child psychiatry and in dealing with pregnant and suicidal patients. Key words: antidepressant, GP knowledge, psychosocial treatment, psychotherapy.

Australian and New Zealand Journal of Psychiatry 2001; 35:827–832

John W G Tiller, Professor (Correspondence)

Department of Psychiatry, The University of Melbourne, Albert Road Clinic, 31–33 Albert Road, Victoria 3004, Australia

Jerzy Krupinski, Consultant in Health and Health Care Research

Received 13 December 2000; revised 4 May 2001; accepted 4 July 2001.

TREATMENT OF DEPRESSION BY GENERAL PRACTITIONERS828

Methods

General practitioners were asked to complete two questionnaires in a group situation. One questionnaire provided information on the gender and age group of the GPs, year of medical graduation, and type of practice. The other questionnaire asked for information on the level of recognition and management of depression by GPs.

GPs were asked to list symptoms (an open ended question) on the basis of which they would diagnose depression.

Multiple choice questions were used to elucidate the class of anti- depressants they would choose initially, the name and the dose of the antidepressant of choice, the length of treatment and the eventual steps taken if the patient did not respond to the initial treatment.

GPs were asked also to indicate on a five point scale from none to very good the level of knowledge of, and skills in, the various types of treatment of depression in general, and for selected classes of patients.

Following these questions, they were presented with four vignettes describing different types of patients, and asked to make a diagnosis and suggest treatment for each of the four individuals.

Results

Doctors

Altogether 3289 individuals were included in the study of whom 2040 completed both questionnaires. Another 460 doctors completed the main questionnaire, but did not provide the demographic data on themselves, whilst 789 GPs completed only the demographic question- naire. Thus, it was possible to analyse the knowledge in recognition and treatment of depressive illness by 2500 GPs. The comparison of gender, age group and year of graduation of those who completed and did not complete the main questionnaire did not show any differences between the respondents and the nonrespondents to the main question- naires; a higher proportion of respondents worked with one to two partners, while more nonrespondents worked with three or more part- ners. In both groups only one in 10 worked fewer than 20 h weekly.

Of the General Practitioners, 25.3% were females, 73.8% were males, and the remaining 0.9% did not state their gender. In terms of age, 31.3% were under the age of 40, 36.5% were 40–49-year-old, 18.5% were in the 50–59 years age group, and 12.5% were 60 years and over. A higher proportion of respondents worked with one to two partners (32.8 vs. 28.1%), while more nonrespondents worked with three or more partners. One in four of respondents and nonrespon- dents were in a solo rather than group practice (26.7 and 24.1%, respectively).

Proportion of patients with depression

General practitioners were asked to estimate the proportion of their patients with depressive illness. Sixty per cent believed that less than 10% of their patients suffered from depression. Half of these (30%) felt that this proportion was even less than 5%. Less than 10% of the respondents estimated to have 20% or more of their patients presenting with depression and less than 3% believed that this proportion exceeded 40%.

Recognition of depressive illness

We asked the doctors to list symptoms on which they would base the diagnosis of depression. The number of symptoms listed were from none (87 doctors) to 20 or more. These symptoms are listed in descend- ing order of frequency in Table 1. It is interesting to note that 86.8% of respondents listed sleep disorders as diagnostic specific symptoms, whilst depressed mood was mentioned by only slightly over half of the doctors.

To compare their description of depressive symptomatology with the DSM-IV criteria for diagnosing a depressive episode the symptoms reported by the GPs were grouped into the nine listed as criteria for diagnosing a major depressive episode. Five or more of those symp- toms were needed, including depressive mood and/or loss of interest or pleasure. 2117 doctors (84%) mentioned one or both of the two main symptoms, but only 699 of these, or 28% of the total sample, listed at least five criterion symptoms.

Treatment

Over one third of GPs (35.2%) claimed never to rely on pharmaco- logical treatment alone. The most popular treatment was the combina- tion of pharmacological and nonpharmacological treatment: almost 60% of doctors used it in more than half of their patients (Figure).

Almost three fifths of respondents (56.3%) relied on tricyclic anti- depressants, dothiepin being the most commonly named drug from this group. Monoamine oxidase inhibitors (MAOI) and tetracyclic drugs

Figure 1. The proportion of doctors reporting the frequency of use of each of three types of treatment. (a)

Medication only; (b) Non-pharmacological only;(c) Non-pharmacological and medication. �, Nil;

, 1–19%; �, 20–49%; , >50%.

J. KRUPINSKI AND J.W.G. TILLER 829

were selected as drug of choice by 0.1 and 2.3% respondents, respec- tively. Selective serotonin uptake inhibitors (SSRI) and reversible inhibitors of monoamine oxidase (RIMA) were chosen by one fifth of doctors each. Only 77 (3.1%) did not respond to this question. Very few doctors recommended doses below or above the recommended thera- peutic range. Paroxetine and sertraline were recommended more often in the low end of the therapeutic range, whilst the opposite was true for moclobemide. This is consistent with current teaching on the use of these agents.

Almost two thirds of GPs report they would refer fewer than 1 in 5 of their depressed patients to psychiatrists. This is consistent with the current practice of primary community care [3].

Almost all GPs involved other family members in the therapeutic process while slightly fewer reported using other community agencies.

Self assessment of knowledge and skills

Responses to the questions regarding their knowledge and skills in various areas of treatment are presented in Table 2. The doctors claimed moderate and good knowledge and skills in brief and pro- longed counselling, but less in other nonpharmacological treatments.

Some 30% of GPs did not answer this question. In contrast, the majority of the doctors assessed their knowledge and skills in the use of antidepressant medication as good or moderate. They had very little confidence in dealing with children. Two thirds of them described their knowledge in this area as minimal or none. On the other hand, over 90% claimed to have very good, good or moderate knowledge of depression in the elderly. The knowledge and skills to deal with depression with pregnancy, and suicide was reported as moderate.

Vignettes

The GPs were presented with vignettes of four patients, named White, Black, Green and Brown, describing their problems and symp- toms. Mrs White is an elderly widow, who recently lost her husband, whilst Ms Black is a single mother with various psychological and social problems. Mr Green is a 38-year-old man with abdominal com- plaints, who recently lost weight, became anxious and irritable and cannot cope with work, whilst Mrs Brown presented with recurrent depression, from which she has suffered for 15 years. The full descrip- tion of these patients, as presented to the doctors, are given in the appendix.

Table 1. Symptoms Of Which The General Practitioner Based The Diagnosis Of Depression

Description n % Sleep disturbances; insomnia; early wakening 2169 86.8 Loss of appetite; overeating; weight changes 1391 55.6 Depressed mood; hopelessness; sad; gloomy; diagnosed by use of antidepressants 1360 54.4 Apathy; lethargy; tiredness; lassitude 1083 43.3 Loss of interest; withdrawal; indifference; loneliness 901 36.0 Loss of energy; loss of drive; burnt out 745 29.8 Loss of libido; loss of sex drive; impotence 655 26.2 Tears; weeping; crying 642 25.6 Anxious; agitated; irritable; restless, tense; stressed 630 25.2 Feeling worthless; guilty; lack of self esteem 582 23.8 Somatic; vegetative symptoms; malaise; multiple consultations 600 24.0 Suicide thoughts; thought of self injury 535 21.4 Loss of concentration; poor memory, poor thinking 531 21.2 Diminished performance; inability to cope 348 13.9 Emotional lability; mood swings 321 12.8 Loss of affect; flat affect; loss of emotion 238 9.5 Loss of enjoyment or pleasure; lack of humor 179 7.2 Behavioural problems; aggressiveness; behavioural changes 174 7.0 Pessimism; negative attitudes, worrying 174 7.0 Psychomotor retardation; slowness 147 5.9 Headaches; dizziness 120 4.8 Appearance; speech; excessive smiling; vagueness, etc. 103 4.1 Heavy use of alcohol, tobacco or drugs 66 2.6 Delusions; hallucinations; confusion 44 1.8 Reaction to probable causes or life events 44 1.8 Family or past history of depression 32 1.3 Obsessive ideation; phobias 22 0.9 Lack of insight 11 0.4 Period of life (menopause) 10 0.4 Depressive rating scales used to make the diagnosis 5 0.2 Not stated 87 2.7

Whilst the problems of the elderly widow, Mrs White, were diag- nosed mainly as adjustment disorder or uncomplicated bereavement, one third of the GPs felt that the single mother Ms Black is suffering from a major depressive episode. No striking differences are noted between the diagnoses given to Mr Green and Mrs Brown.

Only Mrs Brown is felt to be an extreme suicide risk by the major- ity of doctors, whereas all the others are recorded as at most a possible risk by the majority of doctors. A small proportion of doctors regarded all as extreme risk (0.8% white, 2.3% black, 4.5% green).

Whilst the doctors are confident to treat the elderly widow, and to a lesser extent the single mother, most would refer Mrs Brown to a psy- chiatrist or to a hospital. This was also true to a lesser extent to Mr Green. Except for Mrs Brown, the majority of doctors would use indi- vidual therapy for the other three patients, but would not resort to group or family therapy.

Discussion

The total number of 2500 GPs who completed the main questionnaire is sufficiently large to draw conclusions from the data. Over another 200 questionnaires arrived after the data were already coded and computerised. However, the 783 doctors who did not complete this questionnaire have to be regarded as those possibly with a low insight into depression or low confidence in its assessment and treatment. This should be taken into consideration when the level of recognition and knowl- edge of treatment of depression by GPs is assessed. It is worthwhile to stress that the nonrespondents differed from the respondents only in terms of the size of practice.

TREATMENT OF DEPRESSION BY GENERAL PRACTITIONERS830

Table 2. GPs Self Assessment Of Knowledge And Skills

Very good Good Moderate Minimal None Not Stated n % n % n % n % n % n %

Brief counseling Knowledge 245 9.8 942 37.7 1010 40.4 163 6.5 13 0.5 127 5.1 Skills 212 8.5 903 36.1 1033 41.3 189 7.6 17 0.7 146 5.8

Prolonged counseling Knowledge 147 5.9 629 25.2 1040 41.6 481 19.2 77 3.1 126 5.0 Skills 127 5.1 576 23.0 996 39.8 569 22.8 84 3.4 148 5.9

Other nonpharmacological Knowledge 77 3.1 341 13.6 621 24.8 542 21.7 195 7.8 724 29.0 Skills 66 2.6 278 11.1 556 22.2 607 24.3 252 10.1 741 29.6

Antidepressant medication Knowledge 184 7.4 1155 46.2 969 38.8 67 2.7 2 0.1 123 4.9 Skills 155 6.2 1071 42.8 1056 42.2 83 3.3 2 0.1 133 5.3

Knowledge or skills on depression & its treatment with: Children 34 1.4 128 5.1 662 26.5 1326 53.0 258 10.3 92 3.7 Elderly 201 8.0 1207 48.3 892 35.7 109 4.4 5 0.2 86 3.4 Pregnancy 99 4.0 691 27.6 1046 41.8 503 20.1 68 2.7 93 3.7 Suicide 62 2.5 448 17.9 1178 47.1 638 25.5 79 3.2 95 3.8

Table 3. Diagnostic Categories – Diagnosis

Elderly: Single Gastrointestinal Recurrent lost husband mother complaints depression

(White) (Black) (Green) (Brown) Questionnaire completed 2391 100% 2321 100% 2256 100% 2211 100% Diagnosis n % n % n % n % Major depressive episode 207 8.7 843 36.3 920 40.8 1153 52.1 Major depression with melancholia 126 5.3 136 5.9 912 40.4 901 40.8 Bipolar disorder 8 0.3 18 0.8 51 2.3 111 5.0 Adjustment disorder with depressed mood 1037 43.4 1010 43.5 99 4.4 3 0.1 Neurotic depression 16 0.7 277 11.9 231 10.2 35 1.6 Uncomplicated bereavement 991 41.4 5 0.2 0 – 0 – Not stated 6 0.3 32 1.4 43 1.9 8 0.4

We intentionally left the list of symptoms on which the GPs based the diagnosis of depression as an open-ended question, to avoid any bias from suggesting symptoms listed, for example in the SPHERE depression checklist [4,5] from the researchers. Only 87 GPs did not answer this question. However, responses did not conform to the rigors of the DSM-IV criteria in diagnosing major depressive disorder. GPs relied often on less important or more nonspecific symptoms such as sleep disturbances or weight changes, or even nonspecific items such as anxiety or psychosomatic complaints. However, the DSM criteria refer to a major depressive disorder whilst the GP had a much broader view of the diagnosis of depression [6].

Despite this broad approach to the diagnosis of depres- sion, the estimated proportion of patients with depressive problems in general practice is significantly lower than that suggested by Judd and Burrows [2]. Many authors claim under-recognition of depression by nonpsychiatric medical staff [7–9]. A more recent study [10] of recog- nition of depression by doctors referring hospital patients to a psychiatric consultation-liaison service indicates it is under-diagnosing by nonpsychiatrists, although in a pro- portion of cases the psychiatrist rejected the diagnosis of the referring doctor. It is therefore necessary for the purpose of general practice to widen the criteria to help identify the diagnosis of depression beyond the major depressive episode, and refine both identification and diagnostic skills to ensure that this disorder is neither under-diagnosed nor over-diagnosed.

Tricyclic antidepressants were the drug of choice by over half of the GPs, whilst SSRI and RIMA were selected by one-fifth of the respondents each. MAOI’s were not used at all. Only 3% of doctors did not respond to this question. It is of great satisfaction that only a minute proportion of GPs (0–5%) suggested a non- therapeutic or potentially toxic dose of prescribed medi- cations.

The self-assessment of their knowledge and skills has been taken at its face value. The doctors felt confident about their knowledge and skills in pharmacological and nonpharmacological treatment of depression and about dealing with elderly patients. They felt uncomfortable only in treating children, the pregnant, and suicidal patients, which has to be taken up in their future training. These were addressed in later workshops.

The GP reports of higher referral rates than normally reported from general practice may be because GPs who attended these workshops were more interested in depression than the average and as a result referred more patients to psychiatrists.

The diagnostic vignettes proved to be a good method to determine whether the GPs distinguish between

various types of patients. Whilst the general trend in diagnosing, assessing severity and treatment suggestions were in the right direction, there was a sizeable minority who would over-diagnose and over-treat the bereaved widow or the single mother.

Conclusions

The study has shown that the majority of GPs have a satisfactory insight into recognition and treatment of depression, although a sizeable minority based their diagnosis on somatic symptoms, such as sleep or eating disturbances.

A sizeable minority, however, did not feel confident to complete the questionnaires or based their diagnoses on secondary or nonspecific symptoms. The use of medica- tion is generally satisfactory, although a proportion of doctors would over-treat uncomplicated bereavement. There is a need to improve knowledge in child psychia- try, depression in pregnancy, and in dealing with suicidal patients. A postworkshop analysis will determine the effectiveness of the ‘Insights’ program.

Acknowledgements

We are grateful to all the doctors who took part in these workshops and completed the questionnaires. Mr Alan Mackenzie carried out the computer analysis of the data. The ‘Insights’ depression education program was devel- oped by an independent depression education advisory committee, chaired by Dr JWG Tiller, Dr Robert LIewellyn Jones, Dr Dimity Pond, Dr Geoff Riley, Dr Simon Wilcock, Professor Gordon Johnson, Dr Nick O’Connor, Dr Jonathan Phillips, Dr Mike Theodoros, Dr Anne Sved-Williams, and were assisted by Oxford Clinical Communications.

The educator initiative was supported by an educa- tional grant from Roche Products. Roche Products had no input into the design and content of the education program.

References

1. McLennan W. Mental health and wellbeing: profile of adults, Australia (1997), Commonwealth of Australia, Canberra, 1998.

2. Judd FK, Burrows GD. Affective disorders. In: Beaumont PJV, Hampshire RB, eds. Textbook of Psychiatry, Melbourne: Blackwell Scientific Publications, 1989; 85–98.

3. Harris MF, Silove D, Kehag E et al. Anxiety and depression in general practice patients: prevalence and management. Medical Journal of Australia 1996; 164:526–529.

4. Hickie I, Hadzi-Pavlovic D, Scott E et al. SPHERE. A national depression project. Australasian Psychiatry, 1998; 6:248–250.

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5. Hickie I. An approach to managing depression in general practice. Medical Journal of Australia 2000; 173:106–110.

6. Hickie I. Primary care psychiatry is not specialist psychiatry in general practice. Medical Journal of Australia 1999; 170:171–173.

7. Goldberg RJ, Wallace S, Rothney J, Wartman S. Medical clinic referrals to psychiatric social work. Review of 100 Cases. General Hospital Psychiatry 1984; 6:147–152.

8. Moffic HS, Paykel ES. Depression in medical in-patients. British Journal of Psychiatry 1975; 126:346–353.

9. Rifkin A. Depression in physically ill patients. Don’t dismiss it as ‘understandable’. Postgraduate Medicine 1992; 92:153–154.

10. Clarke DM, McKenzie DP, Smith GC. The recognition of depression in patients referred to a consultation-liaison service. Journal of Psychosomatic Research 1995; 39:327–334.

TREATMENT OF DEPRESSION BY GENERAL PRACTITIONERS832

Appendix

Vignettes

Patient White (lost husband)

Mrs White is 75 years old. Her husband died six weeks ago. She says she is depressed because of his death. She is dressed in black, is tearful, and slowed up. She com- plains of her loneliness, difficulties in sleeping at night and not being able to get interested in anything.

Patient Black (single mother)

Ms Black is 27 years old. She is a single mother with two children aged 4 months and 2 years, from different fathers. She is unemployed and is normally living alone in a state-housing flat. She has had a new boyfriend for the last 2 months but has found he is a gambler with an alcohol problem and he has borrowed all of her small amount of savings from her. She is estranged from her parents and family. Following the birth of the last child she coped all right but over the last month has become depressed, tearful, stressed and not coping with the chil- dren or her household. She has some problems with sleep.

Patient Green (gastrointestinal complaints)

Mr Green is a 38-year-old accountant. He presents with abdominal discomfort, diarrhoea, dry mouth, and

sleeplessness with waking in the night and early waking in the morning. This has gone on for over 2 months and he has lost 5 kilograms in weight. He has not had mucus nor blood in his stools. There is no past history of gastro- intestinal disturbance. He is not coping as he used to at work and is uncharacteristically anxious and irritable. He has lost interest in sport and hobbies.

Patient Brown (recurrent depression)

Mrs Brown is 45 years old. She presents with a recur- rence of depression over 2 months. This is like other episodes she has had over the last 15 years. She had hoped it would just go away. She is depressed, tearful, feels hopeless and beyond help and does not show much animation during interview. She lacks energy and is not keeping up with household tasks. She is slow in her speech and says she is slow in her activities and thoughts as well. Her appetite is down and she says she has lost quite a lot of weight. She feels worse in the morning. Her sex drive has gone and she has no joy in her life. She is tense with episodic panic, palpitations and shortness of breath. She has felt too tired to go out or visit friends, but felt forced to come to see you as she is so down. She does not believe life is worth living any more and fears she may harm herself. She has many old tablets from previous courses of treatment, and there is a firearm in the house. She feels this illness is punishment for not having done all she could have for others. She asks for help.

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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Fig. 1. Depression symptoms at baseline and under stress.

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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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