Journal of Affective Disorders 152-154 (2014) 441–447

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Research report

Psychological coping in depressed outpatients: Association with cortisol response to the combined dexamethasone/CRH test Hiroaki Hori a,c,n, Toshiya Teraishi a, Miho Ota a, Kotaro Hattori a, Junko Matsuo a, Yukiko Kinoshita a, Ikki Ishida a, Anna Nagashima a, Norie Koga a, Teruhiko Higuchi b, Hiroshi Kunugi a,c a

Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan National Center of Neurology and Psychiatry, Tokyo, Japan c CREST (Core Research of Evolutional Science & Technology), JST (Japan Science and Technology Agency), Tokyo, Japan b

art ic l e i nf o

a b s t r a c t

Article history: Received 23 September 2013 Accepted 8 October 2013 Available online 22 October 2013

Background: Depression is associated with dysfunctional coping styles and dysregulated hypothalamic– pituitary–adrenal (HPA) axis function. Studies have shown that maladaptive coping strategies relate to abnormal HPA axis function; however, such a relationship has been under-studied in patients with depression. We aimed to examine whether dysfunctional coping styles in depression would be associated with abnormal cortisol reactivity. Methods: Seventy-four outpatients with major depressive disorder and 133 age- and sex-matched healthy individuals were recruited. Coping was assessed by the Ways of Coping Checklist. Psychological distress was assessed by the Hopkins Symptom Checklist. Cortisol reactivity was measured by the combined dexamethasone/corticotropin-releasing hormone test. Results: Compared to healthy individuals, depressed patients demonstrated significantly less use of problem-solving, positive reappraisal and social support coping styles and more use of self-blame and wishful thinking styles. Such a pattern of coping styles was significantly associated with patients' greater distress. Partial correlation analysis in patients, controlling for age and sex, revealed a significant correlation between more use of escape–avoidance coping and lower levels of reactive cortisol measures. A stepwise multiple regression analysis predicting cortisol reactivity from age, sex, distress, symptom severity and coping styles revealed that escape–avoidance coping was a significant predictor. Limitations: The neuroendocrine challenge test was administered only once, based on a simple test protocol. Conclusions: More use of escape–avoidance coping in depressed patients was associated with less cortisol reactivity. Our findings shed light on the heterogeneity of depression in terms of low and high levels of avoidance associated with exaggerated and blunted HPA axis reactivity, respectively. & 2013 Elsevier B.V. All rights reserved.

Keywords: Depression Coping Cortisol DEX/CRH test Stress

1. Introduction Depression is a common mental disorder worldwide, with an estimated 350 million people affected (World Health Organization, 2013). While its pathophysiology remains obscure, psychosocial stress associated with major life events has long been implicated as a precipitating factor of depression (Paykel et al., 1969; Brown and Harris, 1978; Paykel, 2001). Psychological coping, defined as the thoughts and behaviors used to manage the internal and/or external demands of situations that are appraised as stressful (Lazarus, 1993;

n Corresponding author at: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan. Tel.: þ81 42 341 2711; fax: þ81 42 346 1744. E-mail address: [email protected] (H. Hori).

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jad.2013.10.013

Folkman and Moskowitz, 2004), can mediate psychological responses to stressors. Considerable efforts have been made to understand how different coping styles relate to mental health. In general, problemfocused coping strategies have been associated with favorable outcomes while avoidant coping with unfavorable ones (Sugawara et al., 2012). Compared to healthy individuals, depressed patients tend to use problem-focused coping strategies less frequently and emotionfocused ones more frequently (reviewed in Christensen and Kessing, 2005). It is also shown that remitted patients with unipolar depression use more maladaptive coping strategies than do euthymic bipolar disorder patients (Coulston et al., 2013). Such an excessive use of negative coping strategies may even play a causal role in the onset of depressive symptoms (Sawyer et al., 2009). Among a wide range of physiological changes that occur in response to environmental stimuli, the hypothalamic–pituitary– adrenal (HPA) axis reactivity with subsequent cortisol response

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is integrally involved in the response to stressors and the maintenance of homeostasis. Several lines of research have investigated the association between coping styles and HPA axis function (reviewed in Heim et al., 2000). Using the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test (Holsboer et al., 1987; Heuser et al., 1994), a sensitive pharmacological challenge test for the assessment of HPA axis function, we found avoidant coping to be associated with blunted cortisol reactivity in healthy adults (Hori et al., 2010). The HPA axis dysfunction is a well-known biological marker of depression (Holsboer, 2000, 2001; Kunugi et al., 2010). Recently, HPA axis function in depressed patients has been extensively studied using the DEX/CRH test. The aforementioned findings of a relationship between coping and HPA axis function in a nonclinical population, combined with the association of depression with maladaptive coping styles as well as with altered HPA axis function, raise the possibility that dysfunctional coping in depressed patients is related to their abnormal HPA axis function. However, the relationship between coping and cortisol reactivity has been under-studied in depression. Investigating this relation may not only give a clue to understand the pathophysiology of depression in terms of psychobiological interactions but help provide rationale for developing individually-tailored treatment plans as well as for detecting those at risk for depression. With respect to the nature and direction of HPA axis abnormalities, hypocortisolism, as well as hypercortisolism, has been demonstrated in relation to a variety of psychopathology. Correspondingly, while earlier studies have associated depression with elevated cortisol levels and non-suppression to DEX administration, growing evidence indicates that (certain subtypes of) depression can be associated with hypocortisolism (Heim et al., 2000; Gold and Chrousos, 2002; Fries et al., 2005). For example, we have recently reported that personality profiles in depressed patients play a role in determining the direction of HPA axis alteration (Hori et al., 2013). Taken together, it would be of importance to take into account both extreme ends of cortisol levels in investigating HPA axis dysfunction in depression. The present study aimed to examine how different coping strategies are associated with cortisol reactivity to the DEX/CRH test in depressed outpatients. The study hypotheses were that (1) patients would show less use of adaptive coping strategies and more use of maladaptive ones than healthy individuals and (2) such dysfunctional coping styles in patients would be associated with blunted cortisol reactivity, given the finding from our previous DEX/CRH study in healthy individuals (Hori et al., 2010).

2. Methods 2.1. Participants Seventy-four depressed outpatients (age range: 21–58 years; 47 women) were recruited from the outpatient clinic of the National Center of Neurology and Psychiatry (NCNP) Hospital, Tokyo, Japan, or through advertisements in free local magazines and our website announcement. Most of the patients recruited via advertisements or website announcement were regularly attending to a nearby hospital or clinic located in the same geographical area, i.e., the western part of Tokyo. Consensus diagnoses were made based on clinical interviews, observations and case notes by at least two experienced psychiatrists. For those patients under treatment at the NCNP Hospital, the diagnosis was confirmed using the Structured Clinical Interview for DSM-IV Axis I disorders (First et al., 1997). For the remaining patients under treatment at a nearby hospital/clinic, the diagnosis made by his/her attending

doctor was confirmed by the Mini-International Neuropsychiatric Interview (MINI; Sheehan et al., 1998; Otsubo et al., 2005) by a trained research psychiatrist. All met the DSM-IV criteria (American Psychiatric Association, 1994) for major depressive disorder (MDD). Of the total 74 MDD patients, 7 were diagnosed as having comorbid dysthymic disorder. Patients with bipolar disorder were not enrolled. Patients who were in remission, as defined by the total score on the Hamilton Depression Rating Scale 21-item version (HAMD-21) (Hamilton, 1967) of less than 8, were excluded from the study. Patients who were taking carbamazepine were also excluded from the study since it induces dexamethasone metabolism (Privitera et al., 1982). To determine the alteration in coping styles and cortisol reactivity of depressed patients, age- and sex-matched 133 healthy individuals (age range: 20–57 years; 85 women) were recruited as a healthy comparison group from the same geographical area via the free local magazines and our website announcement. All healthy subjects were interviewed using the MINI by a research psychiatrist, and only those who demonstrated no current Axis I psychiatric disorders were enrolled. In addition, those healthy individuals who demonstrated one or more of the following conditions in a non-structured interview performed by an experienced psychiatrist were excluded: past or current regular contact to psychiatric services, having a history of regular use of psychotropics, and presenting other obvious self-reported signs of past primary psychotic and mood disorders. Additional common exclusion criteria for all subjects were as follows: having a prior medical history of central nervous system disease or severe head injury, having a history of substance abuse/ dependence, taking corticosteroids, antihypertensives or oral contraceptives, and being on hormone replacement therapy. The study was approved by the ethics committee of the NCNP, Tokyo, Japan. After the nature of the study procedures had been fully explained, written informed consent was obtained from all participants. 2.2. DEX/CRH test procedure The DEX/CRH test was administered to all participants according to a simple test protocol (Kunugi et al., 2006), which was modified from the original protocol of Heuser et al. (1994). This protocol was described in our previous reports (Hori et al., 2010, 2011, 2013). Briefly, participants took 1.5 mg of DEX (Banyu Pharmaceutical Corporation, Tokyo, Japan) orally at 2300 h. On the next day, a vein was cannulated at 1430 h to collect blood at 1500 h and 1600 h. Human CRH (100 μg) (hCRH ‘Mitsubishi', Mitsubishi Pharma Corporation, Tokyo, Japan) was administered intravenously at 1500 h, immediately after the first blood collection. Plasma concentrations of cortisol were measured by radioimmunoassay at SRL Corporation (Tokyo, Japan). The detection limit for cortisol was 27.59 nmol/l ( ¼1.0 μg/dl). Cortisol values under this limit were treated as 0 nmol/l. Outcome measures of this neuroendocrine test were “DST-Cortisol” (i.e., concentration of cortisol [nmol/l] at 1500 h) and “DEX/CRH-Cortisol” (i.e., concentration of cortisol at 1600 h). To dissect the extent to which each subject's HPA axis responded to the CRH challenge, the magnitude of change from DST-Cortisol to DEX/CRH-Cortisol, namely ΔCortisol, was calculated for each subject. To conduct categorical analyses in addition to dimensional analyses, we employed the cut-off values of cortisol that were identical to those used in our previous report (Hori et al., 2013). Specifically, we defined 3 suppressor groups based on responses to the DEX/CRH test, taking into account the sex differences, as follows. “Incomplete suppressors” was defined as those individuals whose DEX/CRH-Cortisol level was 137.95 nmol/l (¼5.0 μg/dl) or more for men and 273.14 nmol/l or more for women. “Enhanced-suppressors” was defined as those individuals whose DEX/CRH-Cortisol level was

H. Hori et al. / Journal of Affective Disorders 152-154 (2014) 441–447

27.59 nmol/l (¼1.0 μg/dl) or less (i.e., under the detection limit) for men and 49.66 nmol/l or less for women. The remaining subjects were considered to be “moderate-suppressors”.

2.3. Psychological assessment In depressed patients, severity of depressive symptoms was assessed with the HAMD-21 interview. To evaluate psychological coping styles and subjectively perceived psychological distress, two self-report questionnaires were administered to all participants. Coping styles of the participants were assessed using the Japanese version (Nakano, 1991) of the Ways of Coping Checklist (WCCL; Folkman and Lazarus, 1985), a self-report questionnaire consisting of 47 items which measure each participant's preferred coping styles using a four-point scale of frequency, with “not used” being scored 0, “not frequently used”, 1, “sometimes used”, 2, and “regularly used”, 3. The 47 items are grouped into 6 coping strategies, namely problemsolving, positive reappraisal, social support, self-blame, wishful thinking, and escape–avoidance (Nakano, 1991). Subjectively perceived psychological distress was assessed via the Hopkins Symptom Checklist (HSCL; Derogatis et al., 1974), a self-report questionnaire consisting of 58 (or 54) items which are scored on 5 underlying symptom dimensions, i.e., somatization, obsessive–compulsive, interpersonal sensitivity, anxiety, and depression symptoms. In the present study, a validated Japanese version (Nakano, 2005) of the HSCL comprising 54 items was used. In this questionnaire, subjects were instructed to rate each item based on the distress perceived during the previous week, using a four-point scale of frequency, with “not-at-all” being scored 1, “occasionally”, 2, “sometimes”, 3, and “frequently”, 4.

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3. Results 3.1. Demographic/clinical characteristics, psychological measures and cortisol indices of patients and controls Demographic/clinical characteristics, symptom dimensions and cortisol indices of depressed patients and healthy controls are shown in Table 1. Depressed patients and healthy controls did not differ significantly in age, sex distribution, education years, or smoking status. In depressed patients, age and education were not significantly correlated with any of the 3 cortisol indices (all P 40.1). Female patients showed significantly higher DEX/CRH-Cortisol (t [72] ¼ 3.06, P ¼0.003) and ΔCortisol (t [72]¼ 2.85, P ¼0.006), but not DSTCortisol (Mann–Whitney U¼ 715.5, P¼ 0.34), than male patients. Patients who smoke and those who do not did not significantly differ in any of the 3 cortisol indices (all P4 0.1). Clinical variables, including comorbid dysthymic disorder, age of onset, psychiatric hospitalization and medication (i.e., antipsychotics, antidepressants, lithium and benzodiazepines), were not significantly associated with any of the 3 cortisol indices (all P 40.05). Symptomatology of patients, including the HAMD-21 total score and 5 HSCL dimensions, was not significantly correlated with any of the 3 cortisol indices (all P4 0.05). Patients showed significantly more distressing symptoms in all of the 5 HSCL dimensions than controls, as expected (Table 1). Among the 6 WCCL subscales, patients demonstrated significantly less use of problem-solving, positive reappraisal and social support coping styles and more use of self-blame and wishful thinking strategies (Fig. 1). No significant difference was seen in escape– avoidance. DST-Cortisol was significantly higher in patients than in controls while no significant differences were found for the other 3 cortisol indices, namely DEX/CRH-Cortisol, ΔCortisol or suppression pattern (Table 1).

2.4. Statistical analyses 3.2. Correlations between coping and distress in patients Averages are reported as means7standard deviation (SD), or median (range) where appropriate. Non-parametric tests were used to examine the association of DST-Cortisol with other variables, given that this cortisol index fell under the detection limit in a substantial portion of subjects and thus the data did not satisfy the assumptions for parametrical testing; while DEX/CRH-Cortisol and ΔCortisol were examined using parametric tests. The t-test or Mann–Whitney U-test was used to examine differences between two groups. Categorical variables were compared using the χ2 test. Spearman's ρ was used to examine correlations for DST-Cortisol; while partial correlation analysis, controlling for confounders, was performed to examine correlations of DEX/CRH-Cortisol and ΔCortisol with other continuous variables. Since age and sex have been reported to significantly influence cortisol levels (Künzel et al., 2003; Kunugi et al., 2006), these variables were considered as potential confounders regardless of the present data. Correlations among psychological measures were calculated using the partial correlation analysis, controlling for age and sex. The analysis of covariance (ANCOVA), followed by post-hoc pairwise comparisons with Bonferroni correction, was performed to examine differences between the 3 suppressor groups, controlling for the confounders. Finally, a forward stepwise multiple regression analysis, with inclusion and exclusion P value thresholds of 0.05 and 0.1, respectively, was used to predict the main outcome measure of the DEX/ CRH test (i.e., DEX/CRH-Cortisol), from age, sex, symptom severity (as indicated by the HAMD-21 total score), 5 symptom dimensions of the HSCL and 6 subscales of the WCCL. Statistical significance was set at two-tailed Po0.05. Analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 21.0 (SPSS Japan, Tokyo).

As shown in Table 2, partial correlation analysis between WCCL and HSCL scores in depressed patients, controlling for age and sex, revealed that less use of problem-solving and positive reappraisal coping strategies and more use of self-blame, wishful thinking and escape–avoidance coping were significantly associated with more distressing symptoms. The coping strategy of seeking social support was not significantly associated with any distress subscale. 3.3. Relationships between coping and cortisol levels in patients Table 3 presents correlation coefficients between WCCL scores and DEX/CRH test results in depressed patients. Wishful thinking was significantly negatively correlated with DST-Cortisol and escape–avoidance was significantly negatively correlated with the reactive cortisol indices after CRH challenge, namely DEX/CRHCortisol and ΔCortisol. The ANCOVA comparing the 6 WCCL subscales between the 3 suppressor groups of depressed patients, controlling for age and sex, showed that main effect of suppressor group was significant for escape–avoidance [F(2,69) ¼ 3.79, P ¼0.027]. Post-hoc pairwise comparison with Bonferroni correction revealed that incompletesuppressors used significantly less escape–avoidance than moderatesuppressors (estimated mean difference in scaled score: 0.37, 95% confidence interval: 0.04–0.70, P¼0.023). Fig. 2 contrasts the distribution of escape–avoidance scores between incomplete- vs. enhanced-suppressors, showing that the scores were overall lower in incomplete-suppressors. This figure also indicates that, compared to the average level of escape–avoidance in healthy individuals, the majority (62%) of incomplete-suppressors of patients showed lower

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Table 1 Demographic/clinical variables, symptom dimensions and cortisol indices of depressed patients and healthy controls. Variable

Depressed patients (n¼ 74)

Age, years: mean 7 SD Sex, women: n (%) Education, years: mean7 SD Smoking: yes, n (%) Comorbid dysthymic disorder: yes, n (%) Age at onset, years: mean 7 SD Lifetime hospitalization to psychiatric ward: yes, n (%) Lifetime electroconvulsive therapy: yes, n (%) Medication: yes, n (%) Antipsychotic Antidepressant Lithium Benzodiazepine HAMD-21 total score: mean 7 SD Hopkins Symptom Checklist Somatization: mean7 SD Obsessive–compulsive: mean 7 SD Interpersonal sensitivity: mean 7 SD Anxiety: mean 7SD Depression: mean 7 SD Dexamethasone/CRH test DST-Cortisol (nmol/l):a median (range) DEX/CRH-Cortisol (nmol/l): mean 7 SD ΔCortisol (nmol/l): mean 7 SD Suppression pattern, incomplete/moderate/enhanced-suppressors: n

Healthy controls (n¼ 133)

Analysis Statistic

df

P

t ¼0.84 x2 ¼ 0.003 t ¼1.33 x2 ¼ 0.22

205 1 205 1

0.40 0.96 0.19 0.64

104 205 128 123 121

o 0.001 o 0.001 o 0.001 o 0.001 o 0.001

39.3 7 10.1 47 (63.5) 14.9 7 1.9 20 (27.0) 7 (9.5) 31.2 7 11.8 12 (16.2) 1 (1.4)

40.6 711.1 85 (63.9) 15.3 7 2.5 32 (24.1) N.A. N.A. N.A. N.A.

20 (27.0) 57 (77.0) 5 (6.8) 51 (68.9) 15.3 7 5.8

N.A. N.A. N.A. N.A. N.A.

30.0 7 7.6 25.7 7 5.6 23.6 7 6.0 17.2 7 4.4 33.67 7.0

19.9 7 4.6 17.17 5.1 15.9 7 4.9 10.9 7 3.5 19.7 7 5.3

t ¼10.4 t ¼11.2 t ¼9.46 t ¼10.5 t ¼14.9

30.3 (0.0–364.2)

0.0 (0.0–154.5)

161.0 7 143.2 132.3 7 134.5 21/38/15

144.6 7142.2 126.17 132.4 30/76/27

Mann–Whitney U ¼5803.5 t ¼0.79 t ¼0.32 x2 ¼ 0.94

0.020 205 0.43 205 0.75 2 0.62

Abbreviations: CRH, corticotropin-releasing hormone; HAMD-21, 21-item version of the Hamilton Depression Rating Scale; N.A., not applicable. a

Data for 31 patients (41.9%) and 80 controls (60.2%) fell under the detection limit (i.e., less than 27.59 nmol/l).

2.5

*

***

**

***

Depressed patients (n = 74) Healthy individuals (n = 133)

Scaled score

2.0

** 1.5 1.0 0.5 0.0

Fig. 1. Mean scores of the 6 subscales of the Ways of Coping Checklist in depressed patients (n¼ 74) and healthy individuals (n¼ 133). nPo0.05; nnPo0.01; nnnPo0.001 (by t-test). Error bars represent standard errors of the mean.

escape–avoidance whereas the opposite was true for enhancedsuppressors (27%).

3.4. Prediction of cortisol reactivity from demographics, symptoms, distress and coping in patients Table 4 summarizes results of the forward stepwise multiple regression analysis in depressed patients to predict DEX/CRHCortisol from age, sex, depressive symptoms (i.e., HAMD-21 total score), 5 HSCL dimensions and 6 WCCL subscales. The procedure terminated at step 3, explaining 22% of the variance in DEX/CRHCortisol. Being female was a significant positive predictor in all models. Escape–avoidance was found to be a significant negative predictor in the latter models.

4. Discussion Our findings can be summarized as follows: (1) compared to coping styles of healthy individuals, those of depressed patients were overall negative and related to greater distressing symptoms and (2) in depressed patients, coping strategy of escape–avoidance was significantly associated with blunted cortisol reactivity to the DEX/CRH challenge. A number of studies have reported that specific coping strategies are related to altered HPA axis function (reviewed in Heim et al., 2000). While the observed relationship between more use of escape–avoidant coping and lower cortisol levels is consistent with our DEX/CRH study in a nonclinical population (Hori et al., 2010), previous findings of the relationship between different coping styles/behaviors and cortisol (re)activity have been mixed (Frecska et al., 1988; Nicolson, 1992; Heim et al., 2000; O'Donnell et al., 2008). These controversial findings are likely to be attributable to several factors, and different paradigms of cortisol measurements used in different studies may be a major contributor to the controversy; the paradigms include baseline measurements, negative feedback inhibition (as assessed for example by DEX administration), and reactivity to stressors (here mimicked by pharmacological stress challenge). Another issue to consider would be the heterogeneous etiology of depression, as is further discussed below. Although at first sight the two study hypotheses seem to have been both supported, this was not necessarily the case; frequency of the use of the coping strategy that was significantly associated with cortisol reactivity (i.e., escape–avoidance) in depressed patients was not significantly different between patients and controls. Rather, this frequency varied substantially within depressed patients. The categorical analysis with the 3 suppressor groups made this point more clear, in that the incomplete suppression of cortisol (or exaggerated

H. Hori et al. / Journal of Affective Disorders 152-154 (2014) 441–447

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Table 2 Partial correlation coefficients, controlling for age and sex, between coping styles as assessed by the Ways of Coping Checklist and psychological distress as assessed by the Hopkins Symptom Checklist in depressed patients (n¼ 74).

Problem-solving Positive reappraisal Social support Self-blame Wishful thinking Escape–avoidance

Somatization

Obsessive–compulsive

Interpersonal sensitivity

Anxiety

Depression

 0.27n  0.11 0.00 0.29n 0.23 0.31nn

 0.17  0.35nn 0.14 0.34nn 0.42nnn 0.36nn

 0.22  0.39nnn 0.01 0.50nnn 0.37nn 0.43nnn

 0.15  0.29n 0.09 0.49nnn 0.38nn 0.36nn

 0.28n  0.46nnn  0.02 0.45nnn 0.37nn 0.20

Note: df ¼ 70. n

Po 0.05. Po 0.01. nnn Po 0.001. nn

Table 3 Correlation between coping styles as assessed by the Ways of Coping Checklist and cortisol indices as measured by the DEX/CRH test in depressed patients (n¼ 74).

Problem-solving Positive reappraisal Social support Self-blame Wishful thinking Escape–avoidance

DST-Cortisola

DEX/CRH-Cortisolb

ΔCortisolb

0.00  0.12 0.07  0.14  0.31c  0.12

 0.07  0.16  0.10  0.05  0.19  0.28d

 0.06  0.17  0.16  0.01  0.15  0.30e

Abbreviations: DEX, dexamethasone; DST, dexamethasone suppression test; CRH, corticotropin-releasing hormone. a

Correlation coefficients represent Spearman's ρ. Correlation coefficients represent partial correlation coefficients controlling for age and sex (df ¼70). c P¼ 0.008. d P¼ 0.017. e P ¼0.012. b

Fig. 2. Scatterplot showing scores of escape–avoidance subscale of the Ways of Coping Checklist for incomplete-suppressors (n¼ 21) and enhanced-suppressors (n¼ 15) of depressed patients. The horizontal broken line denotes the mean score of escape–avoidance subscale in healthy controls (n¼ 133).

cortisol reactivity) in depressed patients was associated with less use of avoidant coping while the enhanced suppression (or blunted reactivity) was associated with relatively greater use of it, when compared to the average level of healthy individuals (Fig. 2). These findings suggest the existence of distinct subtypes of depression in terms of low and high levels of avoidant coping linked to exaggerated and blunted cortisol reactivity (respectively), thus supporting

the accumulated evidence for heterogeneity of depression (Chen et al., 2000; Ostergaard et al., 2011). While escape–avoidance is generally accepted to be a maladaptive way of coping, the contextual approach to coping has explicitly argued that coping strategies are not inherently good or bad (Lazarus and Folkman, 1984). That is, a given coping strategy may be effective in one situation but not in another, depending in part on the extent to which the situation is controllable (Folkman and Moskowitz, 2004). Moreover, the context is not static, such that what might be considered effective coping at the outset of a stressful situation may turn out to be ineffective later on (Folkman and Moskowitz, 2004), which suggests the importance of considering the dynamic process of coping and its fit to the demands of the situation. Assuming this, while high levels of avoidant coping may be usually maladaptive, it is also likely that too little use of this coping strategy in the face of a stressful situation that is uncontrollable leads to a depressive state, a scenario typically seen in melancholic depression. This conjecture would be supported by the observed association between less use of avoidant coping and higher cortisol levels. In contrast, more use of this strategy was associated with lower cortisol levels. These findings seem to be consistent with the evidence that melancholic depression relates to hypercortisolism whereas atypical depression can be associated with hypocortisolism (Heim et al., 2000; Gold and Chrousos, 2002; Fries et al., 2005). Indeed, cortisol plays a central regulatory role in termination of the stress response, and pathology occurs when cortisol responses become either excessive or insufficient (Raison and Miller, 2003). With respect to the relative roles of distressing symptoms and coping styles in cortisol activity, the literature has suggested that coping, rather than distress or symptoms, is associated with cortisol responses (Dickerson and Kemeny, 2004; Abelson et al., 2005, 2008). In line with this, we did not find any significant correlation between distress or symptoms and altered cortisol reactivity (except for the result that the obsessive–compulsive symptomatology emerged as a significant predictor in the final step of the regression model). It is tempting to speculate that a persisting pattern of dysfunctional stress adaptation, rather than temporary distress per se, could be an important determinant of HPA axis function. To test this hypothesis, however, longitudinal studies are needed. As for the association between depression and HPA axis function, cortisol levels after the sole administration of DEX, i.e., DST-Cortisol, were significantly higher in depressed patients than in controls, which is in agreement with numerous data from DST studies in depression. However, the present study, using a higher dose of DEX as compared to that used in usual DST studies, was not primarily aimed to investigate the association between depression and DST, and actually cortisol levels fell under the detection limit in a substantial portion of subjects. In contrast, the reactive cortisol

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Table 4 Forward stepwise multiple regression analysis predicting DEX/CRH-Cortisol value from age, sex, depressive symptom, psychological distress and coping styles in depressed patients (n¼ 74). Step/variable

R-squared

Adjusted R-squared

Analysis of variance for regression

Step 1 (Constant) Sex Step 2 (Constant) Sex Escape–avoidance Step 3 (Constant) Sex Escape–avoidance Obsessive–compulsive symptom

0.11

0.10

F (1,72)¼9.35, P¼ 0.003

0.19

0.26

0.16

0.22

Standardized β

B

t

P

 2.77 100.15

0.34

 0.05 3.06

0.96 0.003

108.15 88.16  75.69

0.30  0.27

1.56 2.76  2.52

0.12 0.007 0.014

 80.95 107.15  102.46 7.41

0.36  0.37 0.29

 0.81 3.38  3.32 2.53

0.42 0.001 0.001 0.014

F (2,71) ¼ 8.20, Po 0.001

F (3,70) ¼8.02, P o0.001

Abbreviations: DEX, dexamethasone; CRH, corticotropin-releasing hormone. Note: Depressive symptom was indexed by the total score of 21-item version of the Hamilton Depression Rating Scale, psychological distress consisted of the 5 symptom dimensions of the Hopkins Symptom Checklist, and coping consisted of the 6 subscales of the Ways of Coping Checklist. Sex was coded as 1: “men” and 2: “women”.

indices, including DEX/CRH-Cortisol, ΔCortisol and suppression pattern, were not significantly different between patients and controls. While the initial wave of DEX/CRH studies in patients with depression, most of whom were severely depressed inpatients, showed exaggerated cortisol responses (von Bardeleben and Holsboer, 1991; Heuser et al., 1994; Modell et al., 1997; Kunugi et al., 2004), the present result was in line with recent DEX/CRH studies conducted in relatively mildly ill outpatient populations (Gervasoni et al., 2004; Rydmark et al., 2006; Van Den Eede et al., 2006; Carpenter et al., 2009; Veen et al., 2009; Wahlberg et al., 2009). Here again, it may be necessary to consider the heterogeneity of depression, particularly in these populations. The present study has several limitations. First, since the DEX/ CRH test used here was based on a simple test protocol (i.e., measuring the cortisol level only twice), it may have provided less information on HPA axis function. Besides, we did not measure baseline cortisol levels (i.e., the cortisol level before DEX administration), which prevented us from knowing the extent to which each participant suppressed his/her cortisol in response to the 1.5 mg of DEX. Second, the cross-sectional study did not provide information as to the causality between coping styles and alteration in HPA axis function. Third, we did not collect data on the menstrual cycle or menopausal status in our female participants. While these factors may have influenced their HPA axis function, it is unlikely that they had any impact on long-term coping strategies. Finally, since most of our patients were receiving psychotropics, the possibility cannot be ruled out that such medication may have influenced HPA axis function, even though we did not observe any significant relationship between medication and cortisol indices. In conclusion, the present study showed that more use of escape–avoidance coping was significantly associated with blunted cortisol responses to the combined DEX/CRH test in depressed outpatients. Our findings suggest the heterogeneity of depression in terms of low and high levels of avoidant coping associated with exaggerated and blunted cortisol reactivity, respectively. Such evidence might ultimately be translated into biologically-oriented subtyping of depression. Further studies are warranted to pursue this possibility.

Role of funding source HH was supported by JSPS KAKENHI Grant Number 25861041. HK was supported by the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Understanding of molecular and environmental bases for brain health), Intramural Research Grant for

Neurological and Psychiatric Disorders of NCNP, and CREST, JST; these funding sources had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Conflict of interest All authors declare no conflict of interest.

Acknowledgements We wish to thank all volunteers who participated in the study.

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