Scandinavian Journal of Psychology, 2015, 56, 379–383
DOI: 10.1111/sjop.12230
Cognition and Neurosciences Cognitive functioning and cortisol profiles in first episode major depression PIA BERNER HANSSON,1 ROBERT MURISON,1 ANDERS LUND2,3 and ASA HAMMAR1,2,3 1
Department of Biological and Medical Psychology, University of Bergen, Norway Division of Psychiatry, Haukeland University Hospital, University of Bergen, Norway 3 Moodnet Research Group, Haukeland University Hospital, Norway 2
Hansson, P. B., Murison R., Lund, A. & Hammar, A. (2015). Cognitive functioning and cortisol profiles in first episode major depression. Scandinavian Journal of Psychology, 56, 379–383. Major Depressive Disorder (MDD) is often associated with high levels of stress and disturbances in the Hypothalamic Pituitary Adrenal (HPA) system, yielding high levels of cortisol, in addition to cognitive dysfunction. Previous studies have shown a relationship between cortisol profile and cognitive functioning in recurrent MDD in general. More specifically, the association between hypercortisolism and cognitive functioning, such as memory and Executive Functioning (EF), and also more recently cortisol suppression has been explored. However, no studies have investigated these relationships in patients diagnosed with first episode MDD. The aim of the present study was to examine the relationship between cortisol levels before and after the Dexamethasone suppression test (DST) and cognitive function in first episode MDD patients. Twenty-one patients meeting the DSM-IV criteria for a first episode of MDD diagnosis were included in the study. The control group was matched for age, gender and education level. Cortisol was measured in saliva collected with Salivette sampling devices. Saliva samples were collected 4 times during a 24 hours period over two consecutive days: at awakening, after 45 minutes, after 7 hours and at 11 pm. Dexamethasone (1.0 mg) was given orally on Day 1 at 11 pm. The neuropsychological test battery consisted of standardized tests measuring executive functioning (EF) and memory functioning. Cortisol levels did not differ significantly between patients and controls on Day 1, except for the last sample before Dexamethasone administration, where the control group showed higher levels. Both groups showed suppression after Dexamethasone. On Day 2 there was a significant difference between groups at the third sample, showing a significantly lower level in the control group, suggesting that the controls have a more effective suppression profile than the patients. There were no significant correlations between cortisol levels before or after Dexamethasone and cognitive measures. The results indicate impairment on HPA-axis functioning in first episode MDD patients, with less suppression functioning compared to healthy controls, but no relationship between cortisol profile and cognitive functioning in EF or Memory. Key words: First episode Major Depressive Disorder, major depression, cognitive function, cortisol, hypercortisolism, Dexamethasone, suppression, memory, executive function Asa Hammar, Department of Biological and Medical Psychology, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. Fax: -47 5589872; e-mail: [email protected]
INTRODUCTION Major Depressive Disorder (MDD) is often related to acute or chronic stress (Bifulco, Bernazzani, Moran & Ball, 2000; Lupien, McEwen, Gunnar, & Heim, 2009). Acute stress is related to temporary activation of the hypothalamo-pituitary-adrenal (HPA) axis, namely, secretion of corticotropin releasing hormone (CRH) from the hypothalamus, release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, and increased secretion of cortisol from the adrenal cortex. Chronic stress or multiple stress exposures over time are associated with alterations in the HPA axis and its feedback pathways (Claes, 2004; Gallagher, Reid & Ferrier, 2009; Lupien et al., 2009; Pruessner, Kirschbaum, Meinlschmid & Hellhammer, 2003). Hypercortisolism is a typical consequence of a dysregulated negative feedback system in the HPA-axis and down regulated glucocorticoid receptors (GR) and/ or mineralcorticoid receptors (MR) (Holsboer, 2000; Brown, Varghese & McEwen, 2004). Previous studies have shown that hypercortisolism is a condition which is often associated with MDD (Brown et al., 2004; Carroll, Cassidy, Naftolowitz et al., 2007; De Kloet, 2003; Holsboer, Lauer, Schreiber, and Krieg, 1995; Ockenfels, Porter, Smyth, Kirschbaum, Hellhammer & Stone, 1995). One way to measure the efficiency of the negative © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
feedback system of the HPA axis is to administer the GR agonist Dexamethasone (Carroll, 1982; Gallagher et al., 2009). The normal response to Dexamethasone is a suppression of cortisol levels (Carroll, 1982; Gallagher et al., 2009). Both older and more recent studies have shown that depressed patients have either non-suppression, partial suppression, or early escape from suppression compared to healthy controls (Carroll, 1982; Gallagher et al., 2009; Hansson, Murison, Lund & Hammar, 2013). Dysregulated levels of cortisol may lead to atrophies in the brain, specifically in areas such as the hippocampus and the frontal lobes, where densities of GR and MR are high (Lupien et al., 2009), as predicted by the neurotoxicity hypothesis (Sapolsky, Krey & McEwen, 1986). This may represent an underlying mediator of cognitive impairment (Gallagher et al., 2009; Hansson et al, 2013), since the hippocampus is a critical area for the consolidation of learning and memory, and the frontal lobes are important for executive functions (Brown et al., 2004; De Kloet, Vreugdenhil, Oitzl, & Jo€els, 1998; Elliot, 1998; Fossati, Amar, Raox, Ergis, & Allilaire, 1999; Franz, O’Brien, Hauger et al., 2011; Lupien, Gillin, & Hauger, 1999; Stordal, Lundervold, Egeland et al., 2004). Cognitive impairment in MDD has been documented in the literature for decades (for overview see Hammar & Ardal, 2009) and several
380 P. B. Hansson et al. studies have shown that cognitive impairment is associated with dysregulated levels of cortisol, specifically in verbal memory (Egeland, Lund, Landro et al., 2005; Gomez, Fleming, Keller et al., 2006; Hansson et al., 2013; Hinkelmann, Moritz, Botzenhardt et al., 2009; Van Londen, Goekoop, Zwinderman, Lanser, Wiegant & De Wied, 1998) and in executive function (Rubinow, Post, Savard, & Gold, 1984; Egeland et al., 2005). However, several studies find no such association (Michopoulos, Zervas, Pantelis et al., 2008; Gomez, Posener, Keller, DeBattista, Solvason & Schatzberg, 2009; Schlosser, Wolf, Fernando et al., 2010). The deviant findings in the MDD literature might be explained by methodological factors, such as different approaches to measure cortisol, treatment, such as antidepressants, the variety of neuropsychological measures chosen, as well as by diversity in diagnostic criteria, such as including both patients with recurrent MDD and first episode MDD (Hammar & Ardal, 2009). Schmid and Hammar (2013) have recently reported in a previous study that a group of first episode patients show cognitive deficits compared to healthy controls. Following this finding, we investigated the relation between cortisol and cognitive functioning in these first episode patients. To our knowledge no previous study has investigated this relation in first episode MDD. The aim of the present study was to examine the relationship between cortisol levels before and after Dexamethasone administration, that is, suppression, and cognitive function in first episode unipolar MDD patients. In an earlier study with a group of recurrent MDD patients, findings indicated impaired suppression after Dexamethasone administration in the patient group compared to the controls. Moreover, this correlated with impaired memory function (Hansson et al., 2013). However, hypercortisolism was not found in this patient group, which might be explained by the fact that the majority of the patients were treated with antidepressants (Hinkelmann, Moritz, Botzenhardt et al., 2012). To our knowledge, no previous studies have so far investigated cortisol levels, suppression and cognitive function in a group of patients with a first episode of MDD. By examining such a group of patients, one might enhance the knowledge regarding the HPAaxis feedback system in early phases of this disorder in order to plan rehabilitation and treatment in subgroups of MDD (Lupien et al., 2009). We predicted that first episode MDD patients would be affected but, however, not as affected in the HPA-axis compared to recurrent MDD patients, due less stress exposure over time. Thus, we expected there to be no associations between cortisol profiles and cognitive functioning in first episode patients.
METHOD
Scand J Psychol 56 (2015) Table 1. Clinical and demographic variables for the patient group and the control group
Age Education Total IQ MADRS score** Months depressed
Patient group M
N = 21 SD
Control group M
N = 21 SD
25.6 14 117 24.4 1.7
6 1.6 8 4 1.5
25.3 14 120 *** ***
5.5 1.4 9 *** ***
Notes: **Patients were screened at testing; ***Healthy control group, no history of mental illness. structural rating scale the Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 1979) was administered. Inclusion criteria for the patient group were a diagnosis of first episode MDD, and a minimum score of 20 on MADRS, indicating a moderate to severe depression. Patients who had been diagnosed with, or who were receiving treatment for, depression earlier in life were excluded from the study. In addition, patients with known brain damage, severe somatic disorders (including endocrine disorders, autoimmune disorders, ongoing infections and cancer), pregnancy, alcohol and/or substance abuse, who had been treated with electroconvulsive therapy (ECT), or who were psychotic, or had experienced psychosis earlier in life were excluded from the study. Patients were included in the study through cooperation with doctors and psychologists in the primary health-care system. At inclusion in the study, the MINI (Leiknes et al., 1999) was administrated to all patients to get a broad evaluation of psychiatric illnesses. The interview was performed by a trained clinical psychologist. Thirteen patients were prescribed antidepressant medication. Twelve of these thirteen patients were prescribed Selective Serotonin Reuptake Inhibitors (SSRI) (Cipralex, Citalopram), while one used a tetracyclic antidepressant (TeCA) (Remeron/Mirtazapine). All patients were outpatients, receiving either medical or psychological treatment, or both, for the first time, or no treatment at all. A control group of 21 subjects were included mainly throughan advertisement at the University of Bergen, all individually matched to the patient group with respect to age, gender and years of education (within a +/ 2 year limit). Exclusion criteria for the control group were a history of brain damage, any severe somatic disorder, pregnancy, any mental disorder and/or alcohol or substance abuse. (See Table 1 for clinical and demographic variables).
Procedure All participants were examined in the test laboratory at the department. The neuropsychological tests were administered by a trained senior test technician. All patients received pre-packed envelopes containing eight marked tubes (Salivette, Sarstedt AG, Numbrecht, Germany) and written instructions on how and when to collect saliva. The envelope also contained a tablet with 1.0 mg of Dexamethasone (Galepharm AG, K€ usnacht, Germany). Samples were delivered to the laboratory for analysis. Informed consent was obtained from all participants prior to testing after information about the study had been given. The study was performed in accordance with the Helsinki Declaration of the World Medical Association Assembly. The Regional Committee for Medical Research Ethics and The Norwegian Data Inspectorate approved the study.
Subjects Twenty one patients (9 males and 12 females) meeting the DSM-IV criteria (American Psychiatric Association, 2000) for a unipolar first episode MDD diagnosis, using the MINI - International Psychiatric Structural Interview (Leiknes, Leganger, Malt & Malt, 1999), were included in the study. To assess the severity of the depression, the © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
Cortisol assessment Cortisol was assessed from saliva collected with the Salivette sampling device. Saliva samples were collected four times during a 24 hour period over two consecutive days (D1 and D2): at awakening (S1), after 45 minutes (S2), after 7 hours (S3) and at 11 pm (S4). The saliva samples
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Cognitive functioning and cortisol in depression 381
were analyzed using enzyme-linked immunosorbent assay. After the last sample on D1, both patients and controls self-administered the 1.0 mg dose of Dexamethasone.
Neuropsychological assessment The neuropsychological test battery consisted of standardized tests measuring cognitive functioning within verbal memory, as well as aspects of executive function and general levels of intellectual ability. The California Verbal Learning Test (CVLT) (Delis, Kaplan & Kramer 2001). This is a verbal learning and memory test which measures acquisition, recall and recognition processes (Basso & Bornstein, 1999). The test is structured to allow the material to be learned thoroughly through repetitions and the subjects are informed that the test is a memory task. The following measures are obtained; Immediate free recall (trial 1), total correct for all five trials, short delay free recall, short delay cued recall, long delay free recall, long delay cued recall, and recognition total correct responses. The Delis Kaplan Executive Function System (D-KEFS) (Delis et al., 2001) is a test battery assessing various aspects of executive function and four tests were used: D-KEFS Verbal Fluency Test (DKFV). This test includes three conditions: (1) Letter Fluency (F, A, and S); (2) Category Fluency (animals’ and boys’ names); and (3) Category Switching (fruit and furniture). Basic cognitive skills measured by this test are vocabulary knowledge, spelling ability and basic attention. Higher level functions are tapped by all three conditions. These are measures of initiation and simultaneous processing. For the specific conditions, systematic retrieval of phonemically similar lexical items (FAS), rapid retrieval of multiple words from a semantic category (Category Fluency), and set shifting (Category Switching) are measured. D-KEFS Color-Word Interference Test (DKCW). DKCW is a version of a Stroop-like paradigm typically used to investigate inhibitory capacity. It contains the following four conditions: (1) Color Naming; (2) Word Reading; (3) Inhibition (the classic Stroop condition); and (4) Inhibition/ Switching. Basic cognitive skills measured by this test are naming of color patches and reading of colored words. Executive functions tapped by this test are inhibition measured by condition 3 and inhibition, mental flexibility (set-shifting) measured by condition 4.
RESULTS Cortisol Cortisol levels. Cortisol data showed significant heterogeneity of variance between groups at D2S1 (F = 6.81, p = 0.013), and D2S4 (F = 6.94, p = 0.012). Raw data were therefore log10 transformed. A two way repeated measures analysis of variance (Group 9 Sample) showed a significant effect of Sample (F (7, 280) = 99.72, p = 0.000), but no Group effect (F (1, 40) = 0.45, n.s.). However, the Group 9 Sample interaction term was significant (F (7, 280) = 2.23, p = 0.032). To control for the variables Gender and Age, an analysis of covariance was performed. Neither Group (F (8, 31) = 1.79, p = 0.17), Gender (F (8, 31) = 1.13, p = 0.374) nor Age (F (8, 31) = 0.59, p = 0.782) effects were significant in the multivariate analysis. Univariate tests showed significant effects of Group at D1S4 and D2S3. The source of the significant interaction term was investigated using multivariate tests of significance for planned comparisons of the D1S4 samples and the D2S1 samples for each group, chosen on the basis of the crossover and our interest in potential differential effects of dexamethasone. The Control © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
Fig. 1. Mean levels of salivary cortisol (nmol/l standard error of the mean) for the depressed patients (DEP) and the healthy control group (CON) on Day 1 and Day 2 from four samples on each day.
subjects showed a significant decrease in cortisol from D1S4 to D2S1 (F (1, 38) = 25.08, p = 0.000), unlike the Depressed group (F (1, 38) = 0.98, p = 0.328). The two groups differed at D1S4 (F (1, 38) = 5.46, p = 0.025), with Controls showing higher levels than Depressives, but not at D2S1 (F (1, 38) = 1.75, p = 0.194). The group difference at D1S4 was confirmed using a Bonferroni test (p = 0.020). Post hoc (Bonferroni) tests also showed a significant difference between groups at D2S3 (p = 0.034), with Depressives showing higher levels than Controls (see Fig. 1). Cortisol awakening response (CAR). A two analysis of variance (Group 9 Day) showed a significant Group effect (F (1, 40) = 5.93, p = 0.019) and Day effect (F (1, 40) = 7.40, p = 0.009), but no interaction (F (1, 40) = 1.76, p = 0.193). Bonferroni post hoc tests showed that Control subjects showed a lower CAR on Day 2 (CAR D2) than on Day 1 (CAR D1), p = 0.040. Analysis of covariance of CAR showed that neither Group (F (2, 37) = 2.901, p = 0.067), Gender (F (2, 37) = 0.73, p = 0.487) nor Age (F (1, 37) = 0.26, p = 0.772) showed significant effects on either day or together. Univariate tests show a trend for a Group effect on Day 1 (F (1, 38) = 3.76, p = 0.060), with Controls having higher CAR than Depressives. Area under the Curve (AUC). Total area under the curve (AUCG) which reflects total hormone output (Pruessner et al., 2003) was calculated for the first three sample points only on each day since these were fixed in relation to awakening, while the fourth sample was fixed by clock time. AUC values were calculated for the periods between awakening and the second sample, and between the second and third samples on each day, and for the total AUCs for each day. Only total AUC’s are reported here. Analysis of covariance with AUCG as the dependent variable and Gender and Age as co-variables show that neither Group, Gender or Age had significant effects on total AUC on Day 1, (F’s (1, 38) = 0.36, 0.26 and 0.03, respectively) or Day 2 (F’s (1, 38) = 0.61, 0.02 and 0.36, respectively). Across the two days, the repeated measure term was significant, F (1, 40) = 254.32, p < 0.000, with both groups showing a decrease. The Group 9 Day effect was not significant (F (1, 40) = 0.64, p = 0.428).
382 P. B. Hansson et al. Correlations between cortisol parameters, memory and executive function Memory. Pearson product-moment correlations were used to test relationships between memory and cortisol parameters. Bonferroni corrections were used to correct for multiple testing. No significant correlations were found between cortisol levels and Verbal Memory. Prior to Bonferroni coorection, over all subjects, CVLT-Trial 1 was positively correlated with both CAR D1 (r = 0.310, p = 0.049) and AUC D1(r = 0.311, p = 0.048). When Depressed patients only were included, none of the correlations were significant. For Control subjects alone, Short Delay Recall was negatively correlated with CAR D1 (r = –0.469, p = 0.037) and AUC D1 (r = 0.474, p = 0.035). Following Bonferroni corrections for multiple testing, none of these remained significant. Executive function. Prior to Bonferroni corrections, in depressed patients only, Letter fluency was positively correlated with cortisol in the morning after dexamethasone administration (r = 0.518, p = 0.016). When Depressed patients only were included, Verbal Fluency correlated positively with CAR D2 (r = 0.595, p = 0.004), AUC D1 (r = –0.546, p = 0.01) and AUC D2 (r = 0.551, p = 0.01). For Controls alone, Switching was positively correlated with CAR D2 (r = 0.511, p = 0.02) and AUC D2 (r = 0.468, p = 0.038). Over all subjects, CAR D1 was positively correlated with Verbal Fluency r = 0.397, p = 0.010) as was AUC D1 (r = 0.455, p = 0.003). CAR D2 was positively correlated with Switching (r = 0.327, p = 0.037). Following Bonferroni corrections for multiple testing, none of these remained significant.
DISCUSSION The findings in the present study showed significant differences in cortisol levels between groups on several measures; in the evening sample before Dexamethasone, the sample between days, and in the afternoon sample after Dexamethasone. First, the evening sample before Dexamethasone showed that the patients had lower levels compared to healthy controls. Further, the results between the samples before and after Dexamethasone showed that healthy controls had a significant decrease of levels, that is, more efficient suppression function compared to patients. Finally, the patients group showed higher levels in the afternoon after Dexamethasone, compared to the healthy controls. No significant associations between cortisol levels and cognitive measures were found in first episode MDD patients. The CAR measures confirmed no hypercortisolism and less suppression in the patient group. The present study did not find hypercortisolism in the patient group. This finding is in line with previous findings with patients suffering from recurrent depression (Hansson et al., 2013). However, the literature is inconsistent, with some studies reporting hypercortisolism in MDD patients and others not (Brown et al., 2004; De Kloet, 2003; Holsboer et al., 1995; Ockenfels et al., 1995). The lack of hypercortisolism in the patient group might be explained by the fact that more than half of the patients were prescribed antidepressant treatment (mainly SSRIs), as it has been suggested that the mechanism of action of antidepressant involves a normalization of the HPA system (Hinkelmann et al. 2012; Zobel et al., 2004). © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
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Regarding suppression, the present study showed findings indicating that the patient group had less suppression after Dexamethasone administration compared to the healthy controls. Compared to previous findings in recurrent MDD patients where the difference between groups was evident earlier in the morning at awakening (Hansson et al., 2013), this was evident in the first episode MDD group later in the afternoon. This suggests that, even early in the course of MDD, the HPA-axis is affected and that the stress hormone cortisol has an impact on the feedback system. Increased vulnerability to new stress might also enhance the risk for developing new episodes. This also supports the importance of diagnosing and treating first episode patients in early phases of the disease. Regarding cortisol and cognitive function, no significant associations were found in first episode MDD patients. This finding is contrary to previous findings in recurrent MDD (Hansson et al., 2013). Taken together, we suggest that this indicates that the duration of MDD and/or exposure to long term stress could be a factor to consider when it comes to the toxic impact on the brain over time. This finding underlines the importance of identifying, diagnosing and treating MDD in the early course of the disease in order to decrease the risk of recurrent episodes, followed by the risk of increased cognitive impairment.
Methodological strengths and limitations Some limitations in the present study must be considered. The sample of first episode MDD patients was small. Thus, one must consider the risk of type II errors and non-significant results must thus be treated with caution. Nevertheless, the present study represents several strengths as well. First, the patient group was well-defined with regard to diagnostic criteria, as well as symptom load. All patients were diagnosed with a unipolar first episode and with a symptom load indicating a moderate to severe depression. Second, the control group was matched for gender, age and education. Third, the cortisol measurements were taken over two days with eight measures, including at awakening rather than at a specific time point for the morning sample. This offered the opportunity to study the cortisol profile with and without Dexamethasone administration. The present study emphasises the importance of studying the HPA axis suppression efficiency and not only cortisol levels and their association to cognitive functioning. Future studies should follow the cortisol profile over time in first episode MDD patients, in order to clarify how the HPA axis feedback system is affected in the different phases of symptom reduction and recovery, and to further explore the neurotoxicity hypothesis in MDD in a long-term perspective.
CONCLUSION The present study revealed three major findings in first episode depression. First, there was no consistent hypercortisolism in the patient group. Second, the suppression function was affected in the patient group and third, there were no associations between cortisol levels and cognitive functioning. This means that although the first episode patients are not yet as affected as recurrent patients, it is still important to consider the impact on
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the HPA-axis and the feedback system in the early course of the disease in order to prevent the risk of developing new episodes and cognitive impairment.
REFERENCES American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders - Revised (4th edn). Washington, DC: APA. Basso, M. R. & Bornstein, R. A. (1999). Relative memory deficits in recurrent versus first-episode major depression on a word-list learning task. Neuropsychology, 13, 557–563. Bifulco, A., Bernazzani, O., Moran, P. M. & Ball, C. (2000). Lifetime stressors and recurrent depression: Preliminary findings of the Adult Life Phase Interview (ALPHI). Social Psychiatry and Psychiatric Epidemiology, 35, 264–275. Brown, E. S., Varghese, F. P. & McEwen, B. S. (2004). Association of depression with medical illness: Does cortisol play a role? Biological Psychiatry, 55, 1–9. Carroll, B. J. (1982). Clinical applications of the Dexamethasone suppression test for endogenous-depression. Pharmacopsychiatria, 15, 19–24. Carroll, B. J., Cassidy, F., Naftolowitz, D., Tatham, N. E., Wilson, W. H., Iranmanesh, A. et al. (2007). Pathophysiology of hypercortisolism in depression. Acta Psychiatrica Scandinavica. Supplementum, 433, 90–103. Claes, S. J. (2004). CRH, stress, and major depression: A psychobiological interplay. Vitamins and Hormones – Advances in Research and Applications, 69, 117–150. De Kloet, E. R. (2003). Hormones, brain and stress. Endocrine Regulation, 37, 51–68. De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S. & Joels, M. (1998). Brain corticosteroid receptor balance in health and disease. Endocrine Reviews, 19, 269–301. Delis, D. C., Kaplan, E. & Kramer, J. H. (2001). D-KEFS Examiners Manual. San Antonio, TX: The Psychological Cooperation US. Egeland, J., Lund, A., Landro, N. I., Rund, B. R., Sundet, K., Asbjornsen, A. I. et al. (2005). Cortisol level predicts executive and memory function in depression, symptom level predicts psychomotor speed. Acta Psychiatrica Scandinavica, 112, 434–441. Fossati, P., Amar, G., Raoux, N., Ergis, A. M. & Allilaire, J. F. (1999). Executive functioning and verbal memory in young patients with unipolar depression and schizophrenia. Psychiatry Research, 89, 171–187. Franz, C. E., O’Brien, R. C., Hauger, R. L., Mendoza, S. P., Panizzon, M. S., Prom-Wormley, E. et al. (2011). Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive functioning: The Vietnam Era Twin Study of Aging. Psychoneuroendocrinology, 36, 1040–1052. Gallagher, P., Reid, K. S. & Ferrier, I. N. (2009). Neuropsychological functioning in health and mood disorder: Modulation by glucocorticoids and their receptors. Psychoneuroendocrinology, 34, S196–207. Gomez, R. G., Fleming, S. H., Keller, J., Flores, B., Kenna, H., DeBattista, C. et al. (2006). The neuropsychological profile of psychotic major depression and its relation to cortisol. Biological Psychiatry, 60, 472–478. Gomez, R. G., Posener, J. A., Keller, J., DeBattista, C., Solvason, B. & Schatzberg, A. F. (2009). Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function. Psychoneuroendocrinology, 34, 1012–1018. Hammar, A. & Ardal, G. (2009). Cognitive functioning in major depression – a summary. Frontiers in Human Neuroscience, 3, 26. Hansson, P., Murison, R., Lund, A. & Hammar, A. (2013). Cognitive functioning and cortisol suppression in recurrent major depression. PsyCh Journal, 2, 167–174. Hinkelmann, K., Moritz, S., Botzenhardt, J., Muhtz, C., Wiedemann, K., Kellner, M. & Otte, C. (2012). Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: A longitudinal study. Psychoneuroendocrinology, 37, 685–692. © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
Cognitive functioning and cortisol in depression 383 Hinkelmann, K., Moritz, S., Botzenhardt, J., Riedesel, K., Wiedemann, K., Kellner, M. & Otte, C. (2009). Cognitive impairment in major depression: Association with salivary cortisol. Biological Psychiatry, 66, 879–885. Holsboer, F. (2000). The stress hormone is back on the map. Current Psychiatry Reports, 2, 454–456. Holsboer, F., Lauer, C. J., Schreiber, W. & Krieg, J. C. (1995). Altered hypothalamic-pituitary-adrenocortical regulation in healthy-subjects at high familial risk for affective-disorders. Neuroendocrinology, 62, 340–347. Leiknes, K. A., Leganger, S., Malt, E. A. & Malt, U. (1999). Mini internasjonalt neuropsykiatrisk intervju. In D. Sheehan, J. Janavs, J. Baker, K. Harnett-Sheenan, E. Knapp & M. Sheehan (Eds.), Mini International Neuropsychiatric Interview. Tampa, FL: University of South Florida. Lupien, S. J., Gillin, C. J. & Hauger, R. L. (1999). Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: A dose-response study in humans. Behavioral Neuroscience, 113, 420–430. Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience, 10, 434–445. Meyers, J. E. & Meyers, K. R. (1995). Rey Complex Figure Test and Recognition Trial. Professional Manual. Odessa, FL: Psychological Assessment Resources Inc. Michopoulos, I., Zervas, I. M., Pantelis, C., Tsaltas, E., Papakosta, V. M., Boufidou, F. et al. (2008). Neuropsychological and hypothalamicpituitary-axis function in female patients with melancholic and nonmelancholic depression. European Archives of Psychiatry and Clinical Neuroscience, 258, 217–225. Montgomery, S. A. & Asberg, M. (1979). New depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382–389. Ockenfels, M. C., Porter, L., Smyth, J., Kirschbaum, C., Hellhammer, D. H. & Stone, A. A. (1995). Effect of chronic stress associated with unemployment on salivary coltisol – overall cortisol-levels, diurnal rhythm, and acute stress reactivity. Psychosomatic Medicine, 57, 460–467. Pruessner, J. C., Kirschbaum, C., Meinlschmid, G. & Hellhammer, D. H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus timedependent change. Psychoneuroendocrinology, 28, 916–931. Rubinow, D. R., Post, R. M., Savard, R. & Gold, P. W. (1984). Cortisol hypersecretion and cognitive impairment in depression. Archives of General Psychiatry, 41, 279–283. Sapolsky, R. M., Krey, L. C. & McEwen, B. S. (1986). The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284–301. Schlosser, N., Wolf, O. T., Fernando, S. C., Riedesel, K., Otte, C., Muhtz, C. et al. (2010). Effects of acute cortisol administration on autobiographical memory in patients with major depression and healthy controls. Psychoneuroendocrinology, 35, 316–320. Schmid, M. & Hammar, A. (2013). Cognitive function in first episode major depressive disorder – poor inhibition and semantic fluency performance. Cognitive Neuropsychiatry, 18, 515–530 Stordal, K. I., Lundervold, A. J., Egeland, J., Mykletun, A., Asbjornsen, A., Landro, N. I. et al. (2004). Impairment across executive functions in recurrent major depression. Nordic Journal of Psychiatry, 58, 41–47. Van Londen, L., Goekoop, J. G., Zwinderman, A. H., Lanser, J. B. K., Wiegant, V. M. & De Wied, D. (1998). Neuropsychological performance and plasma cortisol, arginine vasopressin and oxytocin in patients with major depression. Psychological Medicine, 28, 275–284. Zobel, A. W., Schulze-Rauschenbach, S., von Widdern, O. C., Metten, M., Freymann, N., Grasmader, K. et al. (2004). Improvement of working but not declarative memory is correlated with HPA normalization during antidepressant treatment. Journal of Psychiatric Research, 38, 377–383. Received 16 October 2014, accepted 16 March 2015
DOI: 10.1111/sjop.12230
Cognition and Neurosciences Cognitive functioning and cortisol profiles in first episode major depression PIA BERNER HANSSON,1 ROBERT MURISON,1 ANDERS LUND2,3 and ASA HAMMAR1,2,3 1
Department of Biological and Medical Psychology, University of Bergen, Norway Division of Psychiatry, Haukeland University Hospital, University of Bergen, Norway 3 Moodnet Research Group, Haukeland University Hospital, Norway 2
Hansson, P. B., Murison R., Lund, A. & Hammar, A. (2015). Cognitive functioning and cortisol profiles in first episode major depression. Scandinavian Journal of Psychology, 56, 379–383. Major Depressive Disorder (MDD) is often associated with high levels of stress and disturbances in the Hypothalamic Pituitary Adrenal (HPA) system, yielding high levels of cortisol, in addition to cognitive dysfunction. Previous studies have shown a relationship between cortisol profile and cognitive functioning in recurrent MDD in general. More specifically, the association between hypercortisolism and cognitive functioning, such as memory and Executive Functioning (EF), and also more recently cortisol suppression has been explored. However, no studies have investigated these relationships in patients diagnosed with first episode MDD. The aim of the present study was to examine the relationship between cortisol levels before and after the Dexamethasone suppression test (DST) and cognitive function in first episode MDD patients. Twenty-one patients meeting the DSM-IV criteria for a first episode of MDD diagnosis were included in the study. The control group was matched for age, gender and education level. Cortisol was measured in saliva collected with Salivette sampling devices. Saliva samples were collected 4 times during a 24 hours period over two consecutive days: at awakening, after 45 minutes, after 7 hours and at 11 pm. Dexamethasone (1.0 mg) was given orally on Day 1 at 11 pm. The neuropsychological test battery consisted of standardized tests measuring executive functioning (EF) and memory functioning. Cortisol levels did not differ significantly between patients and controls on Day 1, except for the last sample before Dexamethasone administration, where the control group showed higher levels. Both groups showed suppression after Dexamethasone. On Day 2 there was a significant difference between groups at the third sample, showing a significantly lower level in the control group, suggesting that the controls have a more effective suppression profile than the patients. There were no significant correlations between cortisol levels before or after Dexamethasone and cognitive measures. The results indicate impairment on HPA-axis functioning in first episode MDD patients, with less suppression functioning compared to healthy controls, but no relationship between cortisol profile and cognitive functioning in EF or Memory. Key words: First episode Major Depressive Disorder, major depression, cognitive function, cortisol, hypercortisolism, Dexamethasone, suppression, memory, executive function Asa Hammar, Department of Biological and Medical Psychology, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. Fax: -47 5589872; e-mail: [email protected]
INTRODUCTION Major Depressive Disorder (MDD) is often related to acute or chronic stress (Bifulco, Bernazzani, Moran & Ball, 2000; Lupien, McEwen, Gunnar, & Heim, 2009). Acute stress is related to temporary activation of the hypothalamo-pituitary-adrenal (HPA) axis, namely, secretion of corticotropin releasing hormone (CRH) from the hypothalamus, release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, and increased secretion of cortisol from the adrenal cortex. Chronic stress or multiple stress exposures over time are associated with alterations in the HPA axis and its feedback pathways (Claes, 2004; Gallagher, Reid & Ferrier, 2009; Lupien et al., 2009; Pruessner, Kirschbaum, Meinlschmid & Hellhammer, 2003). Hypercortisolism is a typical consequence of a dysregulated negative feedback system in the HPA-axis and down regulated glucocorticoid receptors (GR) and/ or mineralcorticoid receptors (MR) (Holsboer, 2000; Brown, Varghese & McEwen, 2004). Previous studies have shown that hypercortisolism is a condition which is often associated with MDD (Brown et al., 2004; Carroll, Cassidy, Naftolowitz et al., 2007; De Kloet, 2003; Holsboer, Lauer, Schreiber, and Krieg, 1995; Ockenfels, Porter, Smyth, Kirschbaum, Hellhammer & Stone, 1995). One way to measure the efficiency of the negative © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
feedback system of the HPA axis is to administer the GR agonist Dexamethasone (Carroll, 1982; Gallagher et al., 2009). The normal response to Dexamethasone is a suppression of cortisol levels (Carroll, 1982; Gallagher et al., 2009). Both older and more recent studies have shown that depressed patients have either non-suppression, partial suppression, or early escape from suppression compared to healthy controls (Carroll, 1982; Gallagher et al., 2009; Hansson, Murison, Lund & Hammar, 2013). Dysregulated levels of cortisol may lead to atrophies in the brain, specifically in areas such as the hippocampus and the frontal lobes, where densities of GR and MR are high (Lupien et al., 2009), as predicted by the neurotoxicity hypothesis (Sapolsky, Krey & McEwen, 1986). This may represent an underlying mediator of cognitive impairment (Gallagher et al., 2009; Hansson et al, 2013), since the hippocampus is a critical area for the consolidation of learning and memory, and the frontal lobes are important for executive functions (Brown et al., 2004; De Kloet, Vreugdenhil, Oitzl, & Jo€els, 1998; Elliot, 1998; Fossati, Amar, Raox, Ergis, & Allilaire, 1999; Franz, O’Brien, Hauger et al., 2011; Lupien, Gillin, & Hauger, 1999; Stordal, Lundervold, Egeland et al., 2004). Cognitive impairment in MDD has been documented in the literature for decades (for overview see Hammar & Ardal, 2009) and several
380 P. B. Hansson et al. studies have shown that cognitive impairment is associated with dysregulated levels of cortisol, specifically in verbal memory (Egeland, Lund, Landro et al., 2005; Gomez, Fleming, Keller et al., 2006; Hansson et al., 2013; Hinkelmann, Moritz, Botzenhardt et al., 2009; Van Londen, Goekoop, Zwinderman, Lanser, Wiegant & De Wied, 1998) and in executive function (Rubinow, Post, Savard, & Gold, 1984; Egeland et al., 2005). However, several studies find no such association (Michopoulos, Zervas, Pantelis et al., 2008; Gomez, Posener, Keller, DeBattista, Solvason & Schatzberg, 2009; Schlosser, Wolf, Fernando et al., 2010). The deviant findings in the MDD literature might be explained by methodological factors, such as different approaches to measure cortisol, treatment, such as antidepressants, the variety of neuropsychological measures chosen, as well as by diversity in diagnostic criteria, such as including both patients with recurrent MDD and first episode MDD (Hammar & Ardal, 2009). Schmid and Hammar (2013) have recently reported in a previous study that a group of first episode patients show cognitive deficits compared to healthy controls. Following this finding, we investigated the relation between cortisol and cognitive functioning in these first episode patients. To our knowledge no previous study has investigated this relation in first episode MDD. The aim of the present study was to examine the relationship between cortisol levels before and after Dexamethasone administration, that is, suppression, and cognitive function in first episode unipolar MDD patients. In an earlier study with a group of recurrent MDD patients, findings indicated impaired suppression after Dexamethasone administration in the patient group compared to the controls. Moreover, this correlated with impaired memory function (Hansson et al., 2013). However, hypercortisolism was not found in this patient group, which might be explained by the fact that the majority of the patients were treated with antidepressants (Hinkelmann, Moritz, Botzenhardt et al., 2012). To our knowledge, no previous studies have so far investigated cortisol levels, suppression and cognitive function in a group of patients with a first episode of MDD. By examining such a group of patients, one might enhance the knowledge regarding the HPAaxis feedback system in early phases of this disorder in order to plan rehabilitation and treatment in subgroups of MDD (Lupien et al., 2009). We predicted that first episode MDD patients would be affected but, however, not as affected in the HPA-axis compared to recurrent MDD patients, due less stress exposure over time. Thus, we expected there to be no associations between cortisol profiles and cognitive functioning in first episode patients.
METHOD
Scand J Psychol 56 (2015) Table 1. Clinical and demographic variables for the patient group and the control group
Age Education Total IQ MADRS score** Months depressed
Patient group M
N = 21 SD
Control group M
N = 21 SD
25.6 14 117 24.4 1.7
6 1.6 8 4 1.5
25.3 14 120 *** ***
5.5 1.4 9 *** ***
Notes: **Patients were screened at testing; ***Healthy control group, no history of mental illness. structural rating scale the Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery & Asberg, 1979) was administered. Inclusion criteria for the patient group were a diagnosis of first episode MDD, and a minimum score of 20 on MADRS, indicating a moderate to severe depression. Patients who had been diagnosed with, or who were receiving treatment for, depression earlier in life were excluded from the study. In addition, patients with known brain damage, severe somatic disorders (including endocrine disorders, autoimmune disorders, ongoing infections and cancer), pregnancy, alcohol and/or substance abuse, who had been treated with electroconvulsive therapy (ECT), or who were psychotic, or had experienced psychosis earlier in life were excluded from the study. Patients were included in the study through cooperation with doctors and psychologists in the primary health-care system. At inclusion in the study, the MINI (Leiknes et al., 1999) was administrated to all patients to get a broad evaluation of psychiatric illnesses. The interview was performed by a trained clinical psychologist. Thirteen patients were prescribed antidepressant medication. Twelve of these thirteen patients were prescribed Selective Serotonin Reuptake Inhibitors (SSRI) (Cipralex, Citalopram), while one used a tetracyclic antidepressant (TeCA) (Remeron/Mirtazapine). All patients were outpatients, receiving either medical or psychological treatment, or both, for the first time, or no treatment at all. A control group of 21 subjects were included mainly throughan advertisement at the University of Bergen, all individually matched to the patient group with respect to age, gender and years of education (within a +/ 2 year limit). Exclusion criteria for the control group were a history of brain damage, any severe somatic disorder, pregnancy, any mental disorder and/or alcohol or substance abuse. (See Table 1 for clinical and demographic variables).
Procedure All participants were examined in the test laboratory at the department. The neuropsychological tests were administered by a trained senior test technician. All patients received pre-packed envelopes containing eight marked tubes (Salivette, Sarstedt AG, Numbrecht, Germany) and written instructions on how and when to collect saliva. The envelope also contained a tablet with 1.0 mg of Dexamethasone (Galepharm AG, K€ usnacht, Germany). Samples were delivered to the laboratory for analysis. Informed consent was obtained from all participants prior to testing after information about the study had been given. The study was performed in accordance with the Helsinki Declaration of the World Medical Association Assembly. The Regional Committee for Medical Research Ethics and The Norwegian Data Inspectorate approved the study.
Subjects Twenty one patients (9 males and 12 females) meeting the DSM-IV criteria (American Psychiatric Association, 2000) for a unipolar first episode MDD diagnosis, using the MINI - International Psychiatric Structural Interview (Leiknes, Leganger, Malt & Malt, 1999), were included in the study. To assess the severity of the depression, the © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
Cortisol assessment Cortisol was assessed from saliva collected with the Salivette sampling device. Saliva samples were collected four times during a 24 hour period over two consecutive days (D1 and D2): at awakening (S1), after 45 minutes (S2), after 7 hours (S3) and at 11 pm (S4). The saliva samples
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Cognitive functioning and cortisol in depression 381
were analyzed using enzyme-linked immunosorbent assay. After the last sample on D1, both patients and controls self-administered the 1.0 mg dose of Dexamethasone.
Neuropsychological assessment The neuropsychological test battery consisted of standardized tests measuring cognitive functioning within verbal memory, as well as aspects of executive function and general levels of intellectual ability. The California Verbal Learning Test (CVLT) (Delis, Kaplan & Kramer 2001). This is a verbal learning and memory test which measures acquisition, recall and recognition processes (Basso & Bornstein, 1999). The test is structured to allow the material to be learned thoroughly through repetitions and the subjects are informed that the test is a memory task. The following measures are obtained; Immediate free recall (trial 1), total correct for all five trials, short delay free recall, short delay cued recall, long delay free recall, long delay cued recall, and recognition total correct responses. The Delis Kaplan Executive Function System (D-KEFS) (Delis et al., 2001) is a test battery assessing various aspects of executive function and four tests were used: D-KEFS Verbal Fluency Test (DKFV). This test includes three conditions: (1) Letter Fluency (F, A, and S); (2) Category Fluency (animals’ and boys’ names); and (3) Category Switching (fruit and furniture). Basic cognitive skills measured by this test are vocabulary knowledge, spelling ability and basic attention. Higher level functions are tapped by all three conditions. These are measures of initiation and simultaneous processing. For the specific conditions, systematic retrieval of phonemically similar lexical items (FAS), rapid retrieval of multiple words from a semantic category (Category Fluency), and set shifting (Category Switching) are measured. D-KEFS Color-Word Interference Test (DKCW). DKCW is a version of a Stroop-like paradigm typically used to investigate inhibitory capacity. It contains the following four conditions: (1) Color Naming; (2) Word Reading; (3) Inhibition (the classic Stroop condition); and (4) Inhibition/ Switching. Basic cognitive skills measured by this test are naming of color patches and reading of colored words. Executive functions tapped by this test are inhibition measured by condition 3 and inhibition, mental flexibility (set-shifting) measured by condition 4.
RESULTS Cortisol Cortisol levels. Cortisol data showed significant heterogeneity of variance between groups at D2S1 (F = 6.81, p = 0.013), and D2S4 (F = 6.94, p = 0.012). Raw data were therefore log10 transformed. A two way repeated measures analysis of variance (Group 9 Sample) showed a significant effect of Sample (F (7, 280) = 99.72, p = 0.000), but no Group effect (F (1, 40) = 0.45, n.s.). However, the Group 9 Sample interaction term was significant (F (7, 280) = 2.23, p = 0.032). To control for the variables Gender and Age, an analysis of covariance was performed. Neither Group (F (8, 31) = 1.79, p = 0.17), Gender (F (8, 31) = 1.13, p = 0.374) nor Age (F (8, 31) = 0.59, p = 0.782) effects were significant in the multivariate analysis. Univariate tests showed significant effects of Group at D1S4 and D2S3. The source of the significant interaction term was investigated using multivariate tests of significance for planned comparisons of the D1S4 samples and the D2S1 samples for each group, chosen on the basis of the crossover and our interest in potential differential effects of dexamethasone. The Control © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
Fig. 1. Mean levels of salivary cortisol (nmol/l standard error of the mean) for the depressed patients (DEP) and the healthy control group (CON) on Day 1 and Day 2 from four samples on each day.
subjects showed a significant decrease in cortisol from D1S4 to D2S1 (F (1, 38) = 25.08, p = 0.000), unlike the Depressed group (F (1, 38) = 0.98, p = 0.328). The two groups differed at D1S4 (F (1, 38) = 5.46, p = 0.025), with Controls showing higher levels than Depressives, but not at D2S1 (F (1, 38) = 1.75, p = 0.194). The group difference at D1S4 was confirmed using a Bonferroni test (p = 0.020). Post hoc (Bonferroni) tests also showed a significant difference between groups at D2S3 (p = 0.034), with Depressives showing higher levels than Controls (see Fig. 1). Cortisol awakening response (CAR). A two analysis of variance (Group 9 Day) showed a significant Group effect (F (1, 40) = 5.93, p = 0.019) and Day effect (F (1, 40) = 7.40, p = 0.009), but no interaction (F (1, 40) = 1.76, p = 0.193). Bonferroni post hoc tests showed that Control subjects showed a lower CAR on Day 2 (CAR D2) than on Day 1 (CAR D1), p = 0.040. Analysis of covariance of CAR showed that neither Group (F (2, 37) = 2.901, p = 0.067), Gender (F (2, 37) = 0.73, p = 0.487) nor Age (F (1, 37) = 0.26, p = 0.772) showed significant effects on either day or together. Univariate tests show a trend for a Group effect on Day 1 (F (1, 38) = 3.76, p = 0.060), with Controls having higher CAR than Depressives. Area under the Curve (AUC). Total area under the curve (AUCG) which reflects total hormone output (Pruessner et al., 2003) was calculated for the first three sample points only on each day since these were fixed in relation to awakening, while the fourth sample was fixed by clock time. AUC values were calculated for the periods between awakening and the second sample, and between the second and third samples on each day, and for the total AUCs for each day. Only total AUC’s are reported here. Analysis of covariance with AUCG as the dependent variable and Gender and Age as co-variables show that neither Group, Gender or Age had significant effects on total AUC on Day 1, (F’s (1, 38) = 0.36, 0.26 and 0.03, respectively) or Day 2 (F’s (1, 38) = 0.61, 0.02 and 0.36, respectively). Across the two days, the repeated measure term was significant, F (1, 40) = 254.32, p < 0.000, with both groups showing a decrease. The Group 9 Day effect was not significant (F (1, 40) = 0.64, p = 0.428).
382 P. B. Hansson et al. Correlations between cortisol parameters, memory and executive function Memory. Pearson product-moment correlations were used to test relationships between memory and cortisol parameters. Bonferroni corrections were used to correct for multiple testing. No significant correlations were found between cortisol levels and Verbal Memory. Prior to Bonferroni coorection, over all subjects, CVLT-Trial 1 was positively correlated with both CAR D1 (r = 0.310, p = 0.049) and AUC D1(r = 0.311, p = 0.048). When Depressed patients only were included, none of the correlations were significant. For Control subjects alone, Short Delay Recall was negatively correlated with CAR D1 (r = –0.469, p = 0.037) and AUC D1 (r = 0.474, p = 0.035). Following Bonferroni corrections for multiple testing, none of these remained significant. Executive function. Prior to Bonferroni corrections, in depressed patients only, Letter fluency was positively correlated with cortisol in the morning after dexamethasone administration (r = 0.518, p = 0.016). When Depressed patients only were included, Verbal Fluency correlated positively with CAR D2 (r = 0.595, p = 0.004), AUC D1 (r = –0.546, p = 0.01) and AUC D2 (r = 0.551, p = 0.01). For Controls alone, Switching was positively correlated with CAR D2 (r = 0.511, p = 0.02) and AUC D2 (r = 0.468, p = 0.038). Over all subjects, CAR D1 was positively correlated with Verbal Fluency r = 0.397, p = 0.010) as was AUC D1 (r = 0.455, p = 0.003). CAR D2 was positively correlated with Switching (r = 0.327, p = 0.037). Following Bonferroni corrections for multiple testing, none of these remained significant.
DISCUSSION The findings in the present study showed significant differences in cortisol levels between groups on several measures; in the evening sample before Dexamethasone, the sample between days, and in the afternoon sample after Dexamethasone. First, the evening sample before Dexamethasone showed that the patients had lower levels compared to healthy controls. Further, the results between the samples before and after Dexamethasone showed that healthy controls had a significant decrease of levels, that is, more efficient suppression function compared to patients. Finally, the patients group showed higher levels in the afternoon after Dexamethasone, compared to the healthy controls. No significant associations between cortisol levels and cognitive measures were found in first episode MDD patients. The CAR measures confirmed no hypercortisolism and less suppression in the patient group. The present study did not find hypercortisolism in the patient group. This finding is in line with previous findings with patients suffering from recurrent depression (Hansson et al., 2013). However, the literature is inconsistent, with some studies reporting hypercortisolism in MDD patients and others not (Brown et al., 2004; De Kloet, 2003; Holsboer et al., 1995; Ockenfels et al., 1995). The lack of hypercortisolism in the patient group might be explained by the fact that more than half of the patients were prescribed antidepressant treatment (mainly SSRIs), as it has been suggested that the mechanism of action of antidepressant involves a normalization of the HPA system (Hinkelmann et al. 2012; Zobel et al., 2004). © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
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Regarding suppression, the present study showed findings indicating that the patient group had less suppression after Dexamethasone administration compared to the healthy controls. Compared to previous findings in recurrent MDD patients where the difference between groups was evident earlier in the morning at awakening (Hansson et al., 2013), this was evident in the first episode MDD group later in the afternoon. This suggests that, even early in the course of MDD, the HPA-axis is affected and that the stress hormone cortisol has an impact on the feedback system. Increased vulnerability to new stress might also enhance the risk for developing new episodes. This also supports the importance of diagnosing and treating first episode patients in early phases of the disease. Regarding cortisol and cognitive function, no significant associations were found in first episode MDD patients. This finding is contrary to previous findings in recurrent MDD (Hansson et al., 2013). Taken together, we suggest that this indicates that the duration of MDD and/or exposure to long term stress could be a factor to consider when it comes to the toxic impact on the brain over time. This finding underlines the importance of identifying, diagnosing and treating MDD in the early course of the disease in order to decrease the risk of recurrent episodes, followed by the risk of increased cognitive impairment.
Methodological strengths and limitations Some limitations in the present study must be considered. The sample of first episode MDD patients was small. Thus, one must consider the risk of type II errors and non-significant results must thus be treated with caution. Nevertheless, the present study represents several strengths as well. First, the patient group was well-defined with regard to diagnostic criteria, as well as symptom load. All patients were diagnosed with a unipolar first episode and with a symptom load indicating a moderate to severe depression. Second, the control group was matched for gender, age and education. Third, the cortisol measurements were taken over two days with eight measures, including at awakening rather than at a specific time point for the morning sample. This offered the opportunity to study the cortisol profile with and without Dexamethasone administration. The present study emphasises the importance of studying the HPA axis suppression efficiency and not only cortisol levels and their association to cognitive functioning. Future studies should follow the cortisol profile over time in first episode MDD patients, in order to clarify how the HPA axis feedback system is affected in the different phases of symptom reduction and recovery, and to further explore the neurotoxicity hypothesis in MDD in a long-term perspective.
CONCLUSION The present study revealed three major findings in first episode depression. First, there was no consistent hypercortisolism in the patient group. Second, the suppression function was affected in the patient group and third, there were no associations between cortisol levels and cognitive functioning. This means that although the first episode patients are not yet as affected as recurrent patients, it is still important to consider the impact on
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the HPA-axis and the feedback system in the early course of the disease in order to prevent the risk of developing new episodes and cognitive impairment.
REFERENCES American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders - Revised (4th edn). Washington, DC: APA. Basso, M. R. & Bornstein, R. A. (1999). Relative memory deficits in recurrent versus first-episode major depression on a word-list learning task. Neuropsychology, 13, 557–563. Bifulco, A., Bernazzani, O., Moran, P. M. & Ball, C. (2000). Lifetime stressors and recurrent depression: Preliminary findings of the Adult Life Phase Interview (ALPHI). Social Psychiatry and Psychiatric Epidemiology, 35, 264–275. Brown, E. S., Varghese, F. P. & McEwen, B. S. (2004). Association of depression with medical illness: Does cortisol play a role? Biological Psychiatry, 55, 1–9. Carroll, B. J. (1982). Clinical applications of the Dexamethasone suppression test for endogenous-depression. Pharmacopsychiatria, 15, 19–24. Carroll, B. J., Cassidy, F., Naftolowitz, D., Tatham, N. E., Wilson, W. H., Iranmanesh, A. et al. (2007). Pathophysiology of hypercortisolism in depression. Acta Psychiatrica Scandinavica. Supplementum, 433, 90–103. Claes, S. J. (2004). CRH, stress, and major depression: A psychobiological interplay. Vitamins and Hormones – Advances in Research and Applications, 69, 117–150. De Kloet, E. R. (2003). Hormones, brain and stress. Endocrine Regulation, 37, 51–68. De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S. & Joels, M. (1998). Brain corticosteroid receptor balance in health and disease. Endocrine Reviews, 19, 269–301. Delis, D. C., Kaplan, E. & Kramer, J. H. (2001). D-KEFS Examiners Manual. San Antonio, TX: The Psychological Cooperation US. Egeland, J., Lund, A., Landro, N. I., Rund, B. R., Sundet, K., Asbjornsen, A. I. et al. (2005). Cortisol level predicts executive and memory function in depression, symptom level predicts psychomotor speed. Acta Psychiatrica Scandinavica, 112, 434–441. Fossati, P., Amar, G., Raoux, N., Ergis, A. M. & Allilaire, J. F. (1999). Executive functioning and verbal memory in young patients with unipolar depression and schizophrenia. Psychiatry Research, 89, 171–187. Franz, C. E., O’Brien, R. C., Hauger, R. L., Mendoza, S. P., Panizzon, M. S., Prom-Wormley, E. et al. (2011). Cross-sectional and 35-year longitudinal assessment of salivary cortisol and cognitive functioning: The Vietnam Era Twin Study of Aging. Psychoneuroendocrinology, 36, 1040–1052. Gallagher, P., Reid, K. S. & Ferrier, I. N. (2009). Neuropsychological functioning in health and mood disorder: Modulation by glucocorticoids and their receptors. Psychoneuroendocrinology, 34, S196–207. Gomez, R. G., Fleming, S. H., Keller, J., Flores, B., Kenna, H., DeBattista, C. et al. (2006). The neuropsychological profile of psychotic major depression and its relation to cortisol. Biological Psychiatry, 60, 472–478. Gomez, R. G., Posener, J. A., Keller, J., DeBattista, C., Solvason, B. & Schatzberg, A. F. (2009). Effects of major depression diagnosis and cortisol levels on indices of neurocognitive function. Psychoneuroendocrinology, 34, 1012–1018. Hammar, A. & Ardal, G. (2009). Cognitive functioning in major depression – a summary. Frontiers in Human Neuroscience, 3, 26. Hansson, P., Murison, R., Lund, A. & Hammar, A. (2013). Cognitive functioning and cortisol suppression in recurrent major depression. PsyCh Journal, 2, 167–174. Hinkelmann, K., Moritz, S., Botzenhardt, J., Muhtz, C., Wiedemann, K., Kellner, M. & Otte, C. (2012). Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: A longitudinal study. Psychoneuroendocrinology, 37, 685–692. © 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd
Cognitive functioning and cortisol in depression 383 Hinkelmann, K., Moritz, S., Botzenhardt, J., Riedesel, K., Wiedemann, K., Kellner, M. & Otte, C. (2009). Cognitive impairment in major depression: Association with salivary cortisol. Biological Psychiatry, 66, 879–885. Holsboer, F. (2000). The stress hormone is back on the map. Current Psychiatry Reports, 2, 454–456. Holsboer, F., Lauer, C. J., Schreiber, W. & Krieg, J. C. (1995). Altered hypothalamic-pituitary-adrenocortical regulation in healthy-subjects at high familial risk for affective-disorders. Neuroendocrinology, 62, 340–347. Leiknes, K. A., Leganger, S., Malt, E. A. & Malt, U. (1999). Mini internasjonalt neuropsykiatrisk intervju. In D. Sheehan, J. Janavs, J. Baker, K. Harnett-Sheenan, E. Knapp & M. Sheehan (Eds.), Mini International Neuropsychiatric Interview. Tampa, FL: University of South Florida. Lupien, S. J., Gillin, C. J. & Hauger, R. L. (1999). Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: A dose-response study in humans. Behavioral Neuroscience, 113, 420–430. Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Reviews Neuroscience, 10, 434–445. Meyers, J. E. & Meyers, K. R. (1995). Rey Complex Figure Test and Recognition Trial. Professional Manual. Odessa, FL: Psychological Assessment Resources Inc. Michopoulos, I., Zervas, I. M., Pantelis, C., Tsaltas, E., Papakosta, V. M., Boufidou, F. et al. (2008). Neuropsychological and hypothalamicpituitary-axis function in female patients with melancholic and nonmelancholic depression. European Archives of Psychiatry and Clinical Neuroscience, 258, 217–225. Montgomery, S. A. & Asberg, M. (1979). New depression scale designed to be sensitive to change. British Journal of Psychiatry, 134, 382–389. Ockenfels, M. C., Porter, L., Smyth, J., Kirschbaum, C., Hellhammer, D. H. & Stone, A. A. (1995). Effect of chronic stress associated with unemployment on salivary coltisol – overall cortisol-levels, diurnal rhythm, and acute stress reactivity. Psychosomatic Medicine, 57, 460–467. Pruessner, J. C., Kirschbaum, C., Meinlschmid, G. & Hellhammer, D. H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus timedependent change. Psychoneuroendocrinology, 28, 916–931. Rubinow, D. R., Post, R. M., Savard, R. & Gold, P. W. (1984). Cortisol hypersecretion and cognitive impairment in depression. Archives of General Psychiatry, 41, 279–283. Sapolsky, R. M., Krey, L. C. & McEwen, B. S. (1986). The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284–301. Schlosser, N., Wolf, O. T., Fernando, S. C., Riedesel, K., Otte, C., Muhtz, C. et al. (2010). Effects of acute cortisol administration on autobiographical memory in patients with major depression and healthy controls. Psychoneuroendocrinology, 35, 316–320. Schmid, M. & Hammar, A. (2013). Cognitive function in first episode major depressive disorder – poor inhibition and semantic fluency performance. Cognitive Neuropsychiatry, 18, 515–530 Stordal, K. I., Lundervold, A. J., Egeland, J., Mykletun, A., Asbjornsen, A., Landro, N. I. et al. (2004). Impairment across executive functions in recurrent major depression. Nordic Journal of Psychiatry, 58, 41–47. Van Londen, L., Goekoop, J. G., Zwinderman, A. H., Lanser, J. B. K., Wiegant, V. M. & De Wied, D. (1998). Neuropsychological performance and plasma cortisol, arginine vasopressin and oxytocin in patients with major depression. Psychological Medicine, 28, 275–284. Zobel, A. W., Schulze-Rauschenbach, S., von Widdern, O. C., Metten, M., Freymann, N., Grasmader, K. et al. (2004). Improvement of working but not declarative memory is correlated with HPA normalization during antidepressant treatment. Journal of Psychiatric Research, 38, 377–383. Received 16 October 2014, accepted 16 March 2015
