Psycho-Oncology Psycho-Oncology 23: 1350–1355 (2014) Published online 30 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/pon.3566
Differences in major depressive disorder and generalised anxiety disorder symptomatology between prostate cancer patients receiving hormone therapy and those who are not Christopher F. Sharpley1,2*, Vicki Bitsika3, Addie C. Wootten1,4 and David R. H. Christie1,5 1
Brain-Behaviour Research Group, University of New England, Armidale, New South Wales, Australia Centre for Autism Spectrum Disorders, Bond University, Robina, Queensland, Australia 3 Brain-Behaviour Research Group, Bond University, Gold Coast, Queensland, Australia 4 Australian Prostate Cancer Research Centre, Epworth Hospital, Melbourne, Victoria, Australia 5 Genesis, Tugun, Queensland, Australia 2
*Correspondence to: Brain-Behaviour Research Group, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia. E-mail: [email protected]
Received: 17 December 2013 Revised: 30 March 2014 Accepted: 7 April 2014
Abstract Objective: The aim of this study is to explore the associations between hormone treatment variables and depression, and the nature of depression in prostate cancer (PCa) patients by comparing the severity and symptom profile of anxiety and depression in men who were currently receiving hormone therapy (HT) versus those who were not. Method: Self-reports of anxiety and depression on standardized scales of GAD and major depressive disorder (MDD) were collected from 156 PCa patients across two recruitment sites in Australia. Patients who were currently receiving HT were compared with patients not receiving HT for their severity and symptom profiles on GAD and MDD. Results: Participants receiving HT had significantly higher GAD and MDD total scores than patients who were not receiving HT. In addition, the symptom profiles of these two HT subgroups were differentiated by significantly higher scores on the key criteria for GAD and MDD plus fatigue and sleeping difficulties but not the remaining symptoms of GAD and MDD. However, there were no significant differences between HT subgroups for the degree of functional impairment experienced by these symptoms. Conclusion: Although these data confirm the association between HT and anxiety/depression, the range of GAD and MDD symptoms influenced is relatively restricted. Moreover, functional ability does not appear to be impaired by HT. These findings clarify the ways in which HT affects PCa patients and suggests that a simple total scale score for anxiety and depression may not be as helpful in designing treatment as consideration of the symptomatic profiles of PCa patients receiving HT. Copyright © 2014 John Wiley & Sons, Ltd.
Introduction Although prevalence varies according to study samples, diagnostic procedures and severity, at least 8% of prostate cancer (PCa) patients also experience clinically significant depression [1–3], well above the prevalence of about 2% for older men in general [4,5]. These depressed PCa patients also have increased emergency room visits, hospitalization, outpatient visits and mortality, as well as increased inpatient pharmacy, laboratory and physiotherapy costs, and higher medical and surgical supply costs [3]. Depressed PCa patients are also more likely to suicide during the first year after diagnosis than non-PCa men [6]. Thus, the continued investigation of the associations between patient or treatment variables and depression, and the nature of that depression in PCa patients remains a priority for translational research in psycho-oncology. In terms of factors that might be associated with depression in PCa patients, the experience of receiving a Copyright © 2014 John Wiley & Sons, Ltd.
diagnosis of PCa is extremely stressful [7], perhaps leading to depression in some men. There are suggestions that some aspects of treatment for PCa can also increase vulnerability to depression, particularly hormone therapy (HT), which helps reduce the size of the prostate in readiness for radiotherapy. HT may impair PCa patients’ mood and ability to think clearly [8–11], although the evidence for this is by no means consistent [12,13]. If HT does induce depression, then it may be useful to understand the nature of that depression by following the suggestions for ‘personalized/precision’ medicine that have emerged in recent years [14–17] and that recommend detailed symptomatology assessments so as to build more individualized treatment targets. In addition to that recommendation to collect symptom detail when assessing depression, anxiety also commonly occurs with depression and that comorbidity significantly predicts resistance to treatment [18–20], delayed recovery, poorer quality of life and increased
MDD and GAD in HT
suicide risk [21,22] and has been reported in 10.2% of PCa samples [23]. Therefore, the present study aimed to extend the previous literature by investigating the association between HT and depression and anxiety among PCa patients. In addition, the nature of the anxiety and depression symptomatology that was associated with HT was investigated. To ensure generalizability to the wider literature, standardized scales of generalised anxiety disorder (GAD) and major depressive disorder (MDD) based on DSM-V [24] definitions of GAD and MDD were used, and responses were collected from PCa patients who were, versus those who were not, currently receiving HT.
Methods Participants
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indicate how depression affects their ability to ‘do your work, take care of things at home or get along with other people’ [26]. Anxiety was measured by the GAD7 [28], which was developed from the DSM-IV Text Revision [25] diagnostic criteria for GAD (unchanged for the DSM-V [24]) and which has specificity and sensitivity of .80. However, because it only taps a subset of the full diagnostic criteria for GAD (plus a functional impairment item) and omits the criteria for fatigue, concentration and sleeping, the GAD7 was supplemented by three additional items written in the same format so that all GAD criteria were measured. This procedure was justified on the basis that the current study aimed to investigate GAD symptomatology rather than classify participants according to a total score that was based upon normative data. This revised scale was called the GAD10. Possible scores on the GAD10 range from 0 to 33. As for the PHQ9, the GAD10 includes a global item measuring functional impairment due to anxiety. Participants are asked to respond to PHQ9 and GAD10 items by ticking one of four options: ‘Not at all’, ‘several days’, ‘more than half the days’ and ‘nearly every day’.
A total of 156 PCa patients was recruited from two cancer treatment centres in two states of Australia and provided self-reports of their current treatment. Patients were recruited by a mail out survey to all current PCa patients in each recruitment site, and so participation was decided by the patients themselves, with a 56.7% take-up rate. All participants had histologically proven PCa limited to the primary recruitment site and regional draining lymph nodes using conventional staging investigations and had received information from their GP, a radiation oncologist and a urologist regarding their treatment options, which included HT, radiotherapy and/or surgery as required. Patients were included regardless of the type of HT they had been prescribed; unwillingness to participate in the study or failure to report on their current treatment status was the only exclusion criteria.
Procedures
Measures
Statistical analyses
Background questionnaire: age (in years), living situation (with wife/partner, widowed, separated/divorced and never married), month and year of first diagnosis, past treatments and current treatments (radiotherapy, surgery, HT and none) and present status of their cancer (cancer still present and undergoing initial treatment, no obvious sign of cancer [in remission] and cancer re-occurring after previous treatment). Depression and anxiety: Depression was assessed via the self-report Patient Health Questionnaire-9 (PHQ9). The PHQ9 was developed from the diagnostic criteria for MDD from the DSM-IV Text Revision [25] (these have not changed in the DSM-V [24]) and has been shown to possess excellent validity [26] and specificity and sensitivity (both above 95%). Possible scores on the PHQ9 range from 0 to 27 [27]. The PHQ9 has nine items, which measure the nine diagnostic criteria for MDD and from which the total scores is calculated, plus a functional impairment item, which asks respondents to
Data were analysed via SPSS 20 to describe the distributions of all variables, and Pearson and Spearman correlations were used to test for the associations between variables, depending on the type of data (i.e. for the interval data from standardized questionnaires or for the ordinal data from treatment received or cancer status). Cronbach’s alpha was used to test the internal consistency of the GAD10 and PHQ9. Analyses of variance (ANOVAs) were used to test for the presence of any significant associations between HT and the background variables of age and time since diagnosis; chi-square was used to test for the presence of any significant associations between HT and the background variables of living situation, past and current treatments and current cancer state. ANOVAs were used to test for the effects of HT upon GAD10 and PHQ9 total scores, and multivariate ANOVA (MANOVA) was used to test for the effects of HT upon the multiple items from each of these scales.
Copyright © 2014 John Wiley & Sons, Ltd.
Patients were posted a package including the participant information statement, background questionnaire and copies of the PHQ9 and GAD10, plus a stamped and addressed envelope for return of the questionnaire package. All procedures were approved by the relevant Human Research Ethics Committees. All participants gave written consent to the study.
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Results Sample results Table 1 presents the background data for the sample of 156 PCa patients (recruitment site effects are analysed in the succeeding text). There were no significant correlations between PHQ9 or GAD10 total scores and any of the demographic variables except current treatment (examined in the succeeding text in more detail) at the Bonferroni-corrected error rate of .05/10 = .005, allowing further analyses to focus upon HT effects. A series of chi-square and ANOVAs also showed that there were no significant differences between the HT and non-HT groups on any of the background variables except those of current treatment. The 5% trimmed means for both the PHQ9 and the GAD10 were very similar to the actual means, indicating negligible influence from extreme scores. Reliability (Cronbach’s alpha) for PHQ9 was .895, and for the GAD10, it was .905, supporting further analysis of these data (plus some initial support for the use of the GAD10 in wider contexts). The correlation between PHQ9 total scores and GAD10 total scores was r = .854, p < .001, reflecting the overlap in GAD and MDD symptoms. To test for effects due to current hormone treatment and also determine if recruitment site or cancer status were significant predictors of anxiety or depression, participants who indicated that they were receiving HT or a combination of treatments that included HT (e.g. surgery plus HT and radiotherapy plus HT) were classified as ‘HT’; all other patients were classified as ‘not HT’, including patients who reported that they had previously received HT but were no longer receiving it. Our previous study on that
issue showed that patients who were currently receiving HT were significantly more anxious and depressed than those who were not currently receiving HT or patients who had previously received HT but who were no longer receiving. There were no significant differences in anxiety and depression in patients who had previously received HT compared with patients who had never received HT [29]. Thus, the comparisons reported in the succeeding text were between patients who were currently receiving HT (n = 93) versus those who were not receiving HT (n = 63), with recruitment site and current cancer status as additional independent variables (current cancer status may be a reason for decisions to prescribe HT or not). Separate ANOVAs were conducted on GAD10 and PHQ9 total scores. There were significant HT effects for GAD10 total score (F(1,154) = 4.033, p < .05, partial eta square = .006) and PHQ9 total score (F = 3.121, p < .05, partial eta square = .020), but no significant effects for recruitment site or for current cancer status or for the interaction between HT and recruitment site or current cancer status for either GAD10 or PHQ9 scores. These results indicate that patients who were receiving HT had significantly higher anxiety (GAD10 mean score = 16.790 (SD = 5.347)) and depression (PHQ9 mean score = 14.532 (4.597) than patients who were not receiving HT (GAD10 mean score = 14.640 (4.77); PHQ9 mean score = 12.483 (4.143)) regardless of their recruitment site. However, those analyses did not explore the differences in symptoms or item content between the two HT subgroups. Therefore, MANOVA was conducted separately for the GAD10 and the PHQ9 because of the risk of confounds due to communality in symptoms. Using the
Table 1. Descriptive data from sample (n = 156) Variable Age (years) Time since diagnosis (months) Living situation With wife/partner Widowed Separated/divorced Never married Present cancer status Still present and treated In remission/no signs Recurring Past treatment Radiotherapy Surgery Hormone therapy Combinations of HT No treatment
Mean
SD
Minimum
Maximum
5% trimmed mean
68.10 49.63
6.785 38.81
49 1
84 195
68.236 46.195
N 143 7 4 2
Valid percent 91.6% 4.5% 2.6% 1.3%
26 103 27
16.4% 65.8% 17.8%
18 79 8 46 5
11.6% 50.4% 5.4% 29.5% 3.1%
SD, standard deviation; HT, hormone therapy.
Copyright © 2014 John Wiley & Sons, Ltd.
Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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11 GAD10 items (i.e. the 10 GAD symptoms plus the functionality item) as the dependent variables, and hormone treatment status (HT) as the independent variable, there was a significant main effect for HT (F(11,144) = 2.402 (Wilks Lambda), p < .01, partial eta square = .155). There were significant univariate effects for 5 of the 11 GAD10 items (marked with an asterisk in Table 2), with HT participants having higher scores for each of these items. When the same MANOVA was run on PHQ9 items, there was a significant main effect for HT (F(10,145) = 2.095 (Wilks Lambda), p < .05, partial eta square = .126). There were significant univariate effects for 4 of the 10 PHQ9 items, shown in Table 2 marked with an asterisk. Again, HT patients had higher scores than non-HT participants for each of these four items. Table 3 presents the item content for the GAD10 and PHQ9 items, which showed significant differences between the HT and non-HT groups, and those items that did not show significant differences across HT subgroups.
Discussion The most immediately apparent result from this study of the associations between HT and anxiety and depression is that, although (as expected from the previous literature: [8,9,29]) PCa patients who were currently receiving HT had significantly higher levels of overall anxiety and depression than PCa patients who were not receiving HT, Table 2. Mean (standard deviation) scores in generalised anxiety disorder-10 and Patient Health Questionnaire-9 items across hormone therapy subgroups GAD10 Item Item Item Item Item Item Item Item Item Item Item
No current HT
Current HT
F
p
1 2 3 4 5 6 7 8 9 10 11
1.25 1.13 1.33 1.31 1.20 1.46 1.14 1.68 1.34 1.47 1.28
(.48) (.37) (.56) (.65) (.56) (.67) (.38) (.87) (.64) (.75) (.67)
1.47 (.69) 1.31 (.59) 1.41 (.66) 1.38 (.55) 1.15 (.40) 1.66 (.82) 1.30 (.61) 2.17 (1.00) 1.53 (.73) 1.85 (.91) 1.44 (.77)
5.938 6.022 0.845 0.486 0.304 2.904 4.154 10.444 3.503 8.766 2.292
.016* .015* .358 .487 .582 .090 .043* .002* .063 .004* .132
PHQ9 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Item 10
1.16 1.22 1.49 1.57 1.22 1.15 1.24 1.10 1.06 1.22
(.48) (.51) (.78) (.73) (.57) (.49) (.56) (.40) (.29) (.63)
1.38 (.58) 1.46 (.71) 1.90 (.99) 2.14 (.75) 1.42 (.75) 1.22 (.58) 1.38 (.60) 1.15 (.54) 1.07 (.32) 1.30 (.61)
5.995 5.689 8.873 15.986 3.620 0.695 2.335 0.682 0.090 0.734
.015* .018* .004* .000* .059 .406 .129 .410 .765 .393
*p < .05.
Copyright © 2014 John Wiley & Sons, Ltd.
those differences were not uniform across the spectrum of GAD and MDD symptomatologies. While there is no reason to expect that these two HT subgroups would be different on all symptoms of anxiety and depression, that assumption is often made when comparisons between these two subgroups of PCa patients are made on the basis of total scale scores alone. Instead, it appears from these data that, while the overall direct association between HT and total anxiety and depression scores is confirmed by these data, that finding is not as uniform across the diagnostic criteria for GAD and MDD as is suggested by total scale scores. It is when data were examined at the individual GAD and MDD diagnostic criteria level that this paper extended the previous findings on the association between HT and anxiety/depression. PCa patients who were receiving HT had significantly higher GAD10 and PHQ9 scores for the key diagnostic criteria for GAD and MDD, respectively. That is, for GAD, they reported (a) anxiety and (b) difficulty in controlling that anxiety; for MDD, they reported (a) feeling depressed and (b) anhedonia. As such, these key symptom differences argue for the clinical meaningfulness of the differences between the HT subgroups and further support previous research that reported significantly higher anxiety and depression scores in PCa patients who were receiving HT [11,29]. As well as the key diagnostic criteria for GAD and MDD, HT patients also reported fatigue and difficulty sleeping on both the GAD10 and PHQ9, confirming the presence of these symptoms. HT has been associated with fatigue and sleep difficulties in the past, and these findings concur with those pharmacological data [11]. The symptoms that appear in column 4 of Table 3 are of further interest because they show those aspects of GAD and MDD that are not significantly different between HT versus non-HT subgroups. For GAD, these include tension and restlessness, fear, being easily annoyed or irritated and having difficulty with cognitive tasks. For MDD, they include appetite disturbances, poor self concept, psychomotor agitation/retardation and difficulty with cognitive tasks. Put together (as anxiety and depression are comorbid in PCa patients), these findings suggest that the PCa patient who is receiving HT may feel anxious and unable to control that anxiety, sadness, depression and anhedonia, plus tiredness and having difficulties sleeping. The PCa patient who is not receiving HT is more likely to report a wider range of symptoms of GAD and MDD and will be less likely to meet the cutoff for clinically significant anxiety or depression on standardized scales than his or her peer who is receiving HT. However, the finding that, regardless of the difference in GAD and MDD symptomatology between HT and non-HT PCa patients, there was no significant difference in their reported ability to perform their social, work and recreational activities (i.e. the final ‘impairment’ item in each scale) raises some challenge to the seriousness of Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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Table 3. Generalised anxiety disorder-10 and Patient Health Questionnaire-9 items showing significant differences between hormone therapy (HT) and non-HT subgroups (i) GAD10 Item
Significant differences for HT versus non-HT
Item
1 2 7 8 10
Feeling nervous, anxious or on edge Not being able to stop or control my worrying Feeling afraid as if something awful might happen Getting easily tired and worn out Having trouble sleeping
3 4 5 6 9 11
(ii) PHQ9 1 2
Little interest or pleasure in doing usual activities Feeling down, depressed or hopeless
5 6
3 4
Trouble falling asleep or sleeping too much Feeling tired or having little energy
7 8 9 10
the significantly elevated GAD10 and PHQ9 scores in the HT subgroup. That is, while it is unpleasant to experience the symptoms listed in column 2 of Table 3, the HT patients who reported those symptoms did not also indicate that those symptoms interfered with their ability to function across important areas of their lives. Treatment implications from these data are aligned with the move towards precision or personalized medicine that has been recommended during recent years [16,17]. Within that model, the recommendation to assess separate aspects of the overall GAD and MDD symptomatology for treatment planning and delivery now has received further evidential support from the results of this study. In previous decades, there has been a great deal of discussion regarding the benefits/limitations of using standardized or ‘manualized’ treatments for psychological disorders such as anxiety and depression [30,31]. Although the present findings do not negate the content of those manualized approaches per se, they do indicate a need to go further than some simplistic ‘one size fits all’ therapy recommendations, which assume that all anxiety/depression is the same and that the total score from self-report or interview assessment methodologies is the only metric of interest. By contrast, individual PCa patients’ scores on the various symptoms, which comprise GAD and MDD, can be used as particular indicators of the severity of those symptoms, with specific treatment protocols following the patient’s profile on those symptoms. In a recent review of MDD symptomatology, four distinct ‘clinical content’ subtypes of MDD were defined and described, and each was shown to have different underlying neurobiological pathways and treatment needs as well as discrete symptoms [32,33], and these four subtypes of depression have been shown to differ across PCa patients [34]. Those depression subtypes might therefore form a basis on which to assess and Copyright © 2014 John Wiley & Sons, Ltd.
No significant differences for HT versus non-HT Worrying too much about different things Trouble relaxing Being so restless that it is hard to sit still Becoming easily annoyed or irritable Having difficulty concentrating These feelings interfere with my ability to socialize, work or live my life well Poor appetite or overeating Feeling bad about yourself, or that you are a failure, or have let yourself or your family down Trouble concentrating on things, such as reading the newspaper or watching TV Moving or speaking so slowly that other people have noticed. Or being so fidgety or restless that you have been moving around more than usual Thoughts that you would be better off dead or of hurting yourself in some way These feelings interfere with my ability to socialize, work or live my life well
diagnose depression in PCa patients, especially those receiving HT, and to form specific treatment plans on the basis of those diagnoses. A similar process could be undertaken for GAD. There are some limitations to the results of this study, principally those of generalizability. The sample was recruited from only two treatment recruitment sites in one nation, and therefore, further data collection across different recruitment sites and social–cultural environments would be valuable. Although it is a common limitation in studies such as this one, the sample was self-selected, and therefore, the possibility of sample bias must be acknowledged. Further, although the GAD10 and PHQ9 are based upon the diagnostic criteria for GAD and MDD, there may be some differences in results if clinical interviews were used instead of self-report methods. Although participants were categorized according to current HT or not, there may be differences in anxiety and depression according to the type of HT that patients were receiving, such as orally or via injection, and this might also confound treatment compliance. However, despite these common limitations, the specific symptom differences in GAD and MDD symptoms between PCa patients undergoing HT versus those who were not are described here in some detail for the first time. These findings extend previous understanding of how HT is associated with PCa patients’ anxiety and depression and provide the first report on the actual functional impairment effects that these GAD and MDD symptoms had for PCa patients receiving HT. The fact that those effects were minimally different to those in PCa patients who were not receiving HT provides a new challenge for the translation of research findings to clinical settings and urges further detailed examination of the pathways between HT and patients’ mood states. Many Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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PCa patients receive HT, and understanding how that treatment affects them is a key aspect of good psychooncology treatment.
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Conflict of interest The authors have declared no conflicts of interest.
13. Wiechno P, Sadowska M, Kaliniwski T, Michalski W, Demkow T. Does pharmacological castration as adjuvant therapy for prostate cancer after radiotherapy affect anxiety and depression levels, cognitive function and quality of life? Psycho-Oncology 2013;22: 346–351. 14. Conradi H, de Jonge P, Ormel J. Prediction of the three-year course of recurrent depression in primary care patients: different risk factors for different outcomes. J Affect Disord 2008;105(1–3):267–271. 15. Conradi H, Ormel J, de Jonge P. Symptom profiles of DSM-IV-defined remission, recovery, relapse, and recurrence of depression: the role of the core symptoms. Depress Anxiety 2012;29:638–645. 16. Hart S, Sturmey P, Logan C, McMurran M. Forensic case formulation. Int J Forensic Ment Health 2011;10:118–126. 17. McKnight DL, Nelson RO, Hayes SC, Jarriet RB. Importance of treating individually assessed response classes in the amelioration of depression. Behav Ther 1984;15:315–335. 18. Coryell W, Endicott J, Andreason N, et al. Depression and panic attacks: the significance of overlap as reflected in follow-up and family study data. Am J Psychiatry 1988;145:293–300. 19. Fava M, Uebelacker L, Alpert JE, Nierenberga A, Pavaa J, Rosenbauma J. Major depressive subtypes and treatment responses. Biol Psychiatry 1997;42:568–576. 20. Gaynes B, Magruder K, Burns B, Wagner H, Yarnall K, Broadhead W. Does a coexisting anxiety disorder predict persistence of depressive illness in primary-care patients with major depression? . Gen Hosp Psychiatry 1999;21:158–167. 21. Brown C, Schulberg H, Madonia M, Shear M, Houck P. Treatment outcomes for primary care patients with major depression and lifetime anxiety disorders. Am J Psychiatry 1996;153(10):1293–1300. 22. Vollrath M, Angst J. Outcome of panic and depression in a seven-year follow-up: results of the Zurich study. Acta Psychiatr Scand 1989;80:591–596.
23. Brintzenhofe-Szoc KM, Levin TT, Li Y, Kissane DW, Zabora JR. Mixed anxiety/ depression symptoms in a large cancer cohort: prevalence by cancer type. Psychosomatics 2009;50(4):283–391. 24. APA. Diagnostic and Statistical Manual of Mental Disorders-V. American Psychiatric Association: Washington, DC, 2013. 25. APA. Diagnostic and Statistical Manual of Mental Disorders (4th edn, Text Revision). American Psychiatric Association: Washington, DC, 2000. 26. Kroenke K, Spitzer R, Williams J. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001;16:606–613. 27. Spitzer R, Kroenke K, Williams J, Group PHQPCS. Validation and utility of a selfreport version of PRIME-MD: the PHQ primary care study. JAMA 1999;282(18): 1737–1744. 28. Spitzer R, Kroenke K, Williams B, Lowe B. A brief measure for assessing generalised anxiety disorder. Arch Intern Med 2006;16: 606–613. 29. Sharpley C, Christie D, Bitsika V. Do hormone treatments for prostate cancer cause anxiety and depression? Int J Clin Oncol in press. DOI: 10.1007/s10147-013-0569-y. 30. Wilson G. Manual-based treatments: the clinical application of research findings. Behav Res Ther 1996;34:295–314. 31. Bitsika V, Sharpley CF. Treating the client rather than the symptoms: moving beyond manualised treatments in psychotherapy. Aust J Guid Counsell 2006;16:159–175. 32. Sharpley C, Bitsika V. Differences in neurobiological pathways of four ‘clinical content’ subtypes of depression. Behav Brain Res 2013;256:368–376. 33. Sharpley C, Bitsika V. Validity, reliability and prevalence of four ‘clinical content’ subtypes of depression Behav Brain Res 2014;259: 9–15. 34. Sharpley C, Bitsika V, Christie D. The incidence and causes of different subtypes of depression in prostate cancer patients: implications for cancer care. Eur J Cancer Care 2013;22:815–823. Epub May 28, 2013.
Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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Differences in major depressive disorder and generalised anxiety disorder symptomatology between prostate cancer patients receiving hormone therapy and those who are not Christopher F. Sharpley1,2*, Vicki Bitsika3, Addie C. Wootten1,4 and David R. H. Christie1,5 1
Brain-Behaviour Research Group, University of New England, Armidale, New South Wales, Australia Centre for Autism Spectrum Disorders, Bond University, Robina, Queensland, Australia 3 Brain-Behaviour Research Group, Bond University, Gold Coast, Queensland, Australia 4 Australian Prostate Cancer Research Centre, Epworth Hospital, Melbourne, Victoria, Australia 5 Genesis, Tugun, Queensland, Australia 2
*Correspondence to: Brain-Behaviour Research Group, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia. E-mail: [email protected]
Received: 17 December 2013 Revised: 30 March 2014 Accepted: 7 April 2014
Abstract Objective: The aim of this study is to explore the associations between hormone treatment variables and depression, and the nature of depression in prostate cancer (PCa) patients by comparing the severity and symptom profile of anxiety and depression in men who were currently receiving hormone therapy (HT) versus those who were not. Method: Self-reports of anxiety and depression on standardized scales of GAD and major depressive disorder (MDD) were collected from 156 PCa patients across two recruitment sites in Australia. Patients who were currently receiving HT were compared with patients not receiving HT for their severity and symptom profiles on GAD and MDD. Results: Participants receiving HT had significantly higher GAD and MDD total scores than patients who were not receiving HT. In addition, the symptom profiles of these two HT subgroups were differentiated by significantly higher scores on the key criteria for GAD and MDD plus fatigue and sleeping difficulties but not the remaining symptoms of GAD and MDD. However, there were no significant differences between HT subgroups for the degree of functional impairment experienced by these symptoms. Conclusion: Although these data confirm the association between HT and anxiety/depression, the range of GAD and MDD symptoms influenced is relatively restricted. Moreover, functional ability does not appear to be impaired by HT. These findings clarify the ways in which HT affects PCa patients and suggests that a simple total scale score for anxiety and depression may not be as helpful in designing treatment as consideration of the symptomatic profiles of PCa patients receiving HT. Copyright © 2014 John Wiley & Sons, Ltd.
Introduction Although prevalence varies according to study samples, diagnostic procedures and severity, at least 8% of prostate cancer (PCa) patients also experience clinically significant depression [1–3], well above the prevalence of about 2% for older men in general [4,5]. These depressed PCa patients also have increased emergency room visits, hospitalization, outpatient visits and mortality, as well as increased inpatient pharmacy, laboratory and physiotherapy costs, and higher medical and surgical supply costs [3]. Depressed PCa patients are also more likely to suicide during the first year after diagnosis than non-PCa men [6]. Thus, the continued investigation of the associations between patient or treatment variables and depression, and the nature of that depression in PCa patients remains a priority for translational research in psycho-oncology. In terms of factors that might be associated with depression in PCa patients, the experience of receiving a Copyright © 2014 John Wiley & Sons, Ltd.
diagnosis of PCa is extremely stressful [7], perhaps leading to depression in some men. There are suggestions that some aspects of treatment for PCa can also increase vulnerability to depression, particularly hormone therapy (HT), which helps reduce the size of the prostate in readiness for radiotherapy. HT may impair PCa patients’ mood and ability to think clearly [8–11], although the evidence for this is by no means consistent [12,13]. If HT does induce depression, then it may be useful to understand the nature of that depression by following the suggestions for ‘personalized/precision’ medicine that have emerged in recent years [14–17] and that recommend detailed symptomatology assessments so as to build more individualized treatment targets. In addition to that recommendation to collect symptom detail when assessing depression, anxiety also commonly occurs with depression and that comorbidity significantly predicts resistance to treatment [18–20], delayed recovery, poorer quality of life and increased
MDD and GAD in HT
suicide risk [21,22] and has been reported in 10.2% of PCa samples [23]. Therefore, the present study aimed to extend the previous literature by investigating the association between HT and depression and anxiety among PCa patients. In addition, the nature of the anxiety and depression symptomatology that was associated with HT was investigated. To ensure generalizability to the wider literature, standardized scales of generalised anxiety disorder (GAD) and major depressive disorder (MDD) based on DSM-V [24] definitions of GAD and MDD were used, and responses were collected from PCa patients who were, versus those who were not, currently receiving HT.
Methods Participants
1351
indicate how depression affects their ability to ‘do your work, take care of things at home or get along with other people’ [26]. Anxiety was measured by the GAD7 [28], which was developed from the DSM-IV Text Revision [25] diagnostic criteria for GAD (unchanged for the DSM-V [24]) and which has specificity and sensitivity of .80. However, because it only taps a subset of the full diagnostic criteria for GAD (plus a functional impairment item) and omits the criteria for fatigue, concentration and sleeping, the GAD7 was supplemented by three additional items written in the same format so that all GAD criteria were measured. This procedure was justified on the basis that the current study aimed to investigate GAD symptomatology rather than classify participants according to a total score that was based upon normative data. This revised scale was called the GAD10. Possible scores on the GAD10 range from 0 to 33. As for the PHQ9, the GAD10 includes a global item measuring functional impairment due to anxiety. Participants are asked to respond to PHQ9 and GAD10 items by ticking one of four options: ‘Not at all’, ‘several days’, ‘more than half the days’ and ‘nearly every day’.
A total of 156 PCa patients was recruited from two cancer treatment centres in two states of Australia and provided self-reports of their current treatment. Patients were recruited by a mail out survey to all current PCa patients in each recruitment site, and so participation was decided by the patients themselves, with a 56.7% take-up rate. All participants had histologically proven PCa limited to the primary recruitment site and regional draining lymph nodes using conventional staging investigations and had received information from their GP, a radiation oncologist and a urologist regarding their treatment options, which included HT, radiotherapy and/or surgery as required. Patients were included regardless of the type of HT they had been prescribed; unwillingness to participate in the study or failure to report on their current treatment status was the only exclusion criteria.
Procedures
Measures
Statistical analyses
Background questionnaire: age (in years), living situation (with wife/partner, widowed, separated/divorced and never married), month and year of first diagnosis, past treatments and current treatments (radiotherapy, surgery, HT and none) and present status of their cancer (cancer still present and undergoing initial treatment, no obvious sign of cancer [in remission] and cancer re-occurring after previous treatment). Depression and anxiety: Depression was assessed via the self-report Patient Health Questionnaire-9 (PHQ9). The PHQ9 was developed from the diagnostic criteria for MDD from the DSM-IV Text Revision [25] (these have not changed in the DSM-V [24]) and has been shown to possess excellent validity [26] and specificity and sensitivity (both above 95%). Possible scores on the PHQ9 range from 0 to 27 [27]. The PHQ9 has nine items, which measure the nine diagnostic criteria for MDD and from which the total scores is calculated, plus a functional impairment item, which asks respondents to
Data were analysed via SPSS 20 to describe the distributions of all variables, and Pearson and Spearman correlations were used to test for the associations between variables, depending on the type of data (i.e. for the interval data from standardized questionnaires or for the ordinal data from treatment received or cancer status). Cronbach’s alpha was used to test the internal consistency of the GAD10 and PHQ9. Analyses of variance (ANOVAs) were used to test for the presence of any significant associations between HT and the background variables of age and time since diagnosis; chi-square was used to test for the presence of any significant associations between HT and the background variables of living situation, past and current treatments and current cancer state. ANOVAs were used to test for the effects of HT upon GAD10 and PHQ9 total scores, and multivariate ANOVA (MANOVA) was used to test for the effects of HT upon the multiple items from each of these scales.
Copyright © 2014 John Wiley & Sons, Ltd.
Patients were posted a package including the participant information statement, background questionnaire and copies of the PHQ9 and GAD10, plus a stamped and addressed envelope for return of the questionnaire package. All procedures were approved by the relevant Human Research Ethics Committees. All participants gave written consent to the study.
Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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Results Sample results Table 1 presents the background data for the sample of 156 PCa patients (recruitment site effects are analysed in the succeeding text). There were no significant correlations between PHQ9 or GAD10 total scores and any of the demographic variables except current treatment (examined in the succeeding text in more detail) at the Bonferroni-corrected error rate of .05/10 = .005, allowing further analyses to focus upon HT effects. A series of chi-square and ANOVAs also showed that there were no significant differences between the HT and non-HT groups on any of the background variables except those of current treatment. The 5% trimmed means for both the PHQ9 and the GAD10 were very similar to the actual means, indicating negligible influence from extreme scores. Reliability (Cronbach’s alpha) for PHQ9 was .895, and for the GAD10, it was .905, supporting further analysis of these data (plus some initial support for the use of the GAD10 in wider contexts). The correlation between PHQ9 total scores and GAD10 total scores was r = .854, p < .001, reflecting the overlap in GAD and MDD symptoms. To test for effects due to current hormone treatment and also determine if recruitment site or cancer status were significant predictors of anxiety or depression, participants who indicated that they were receiving HT or a combination of treatments that included HT (e.g. surgery plus HT and radiotherapy plus HT) were classified as ‘HT’; all other patients were classified as ‘not HT’, including patients who reported that they had previously received HT but were no longer receiving it. Our previous study on that
issue showed that patients who were currently receiving HT were significantly more anxious and depressed than those who were not currently receiving HT or patients who had previously received HT but who were no longer receiving. There were no significant differences in anxiety and depression in patients who had previously received HT compared with patients who had never received HT [29]. Thus, the comparisons reported in the succeeding text were between patients who were currently receiving HT (n = 93) versus those who were not receiving HT (n = 63), with recruitment site and current cancer status as additional independent variables (current cancer status may be a reason for decisions to prescribe HT or not). Separate ANOVAs were conducted on GAD10 and PHQ9 total scores. There were significant HT effects for GAD10 total score (F(1,154) = 4.033, p < .05, partial eta square = .006) and PHQ9 total score (F = 3.121, p < .05, partial eta square = .020), but no significant effects for recruitment site or for current cancer status or for the interaction between HT and recruitment site or current cancer status for either GAD10 or PHQ9 scores. These results indicate that patients who were receiving HT had significantly higher anxiety (GAD10 mean score = 16.790 (SD = 5.347)) and depression (PHQ9 mean score = 14.532 (4.597) than patients who were not receiving HT (GAD10 mean score = 14.640 (4.77); PHQ9 mean score = 12.483 (4.143)) regardless of their recruitment site. However, those analyses did not explore the differences in symptoms or item content between the two HT subgroups. Therefore, MANOVA was conducted separately for the GAD10 and the PHQ9 because of the risk of confounds due to communality in symptoms. Using the
Table 1. Descriptive data from sample (n = 156) Variable Age (years) Time since diagnosis (months) Living situation With wife/partner Widowed Separated/divorced Never married Present cancer status Still present and treated In remission/no signs Recurring Past treatment Radiotherapy Surgery Hormone therapy Combinations of HT No treatment
Mean
SD
Minimum
Maximum
5% trimmed mean
68.10 49.63
6.785 38.81
49 1
84 195
68.236 46.195
N 143 7 4 2
Valid percent 91.6% 4.5% 2.6% 1.3%
26 103 27
16.4% 65.8% 17.8%
18 79 8 46 5
11.6% 50.4% 5.4% 29.5% 3.1%
SD, standard deviation; HT, hormone therapy.
Copyright © 2014 John Wiley & Sons, Ltd.
Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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11 GAD10 items (i.e. the 10 GAD symptoms plus the functionality item) as the dependent variables, and hormone treatment status (HT) as the independent variable, there was a significant main effect for HT (F(11,144) = 2.402 (Wilks Lambda), p < .01, partial eta square = .155). There were significant univariate effects for 5 of the 11 GAD10 items (marked with an asterisk in Table 2), with HT participants having higher scores for each of these items. When the same MANOVA was run on PHQ9 items, there was a significant main effect for HT (F(10,145) = 2.095 (Wilks Lambda), p < .05, partial eta square = .126). There were significant univariate effects for 4 of the 10 PHQ9 items, shown in Table 2 marked with an asterisk. Again, HT patients had higher scores than non-HT participants for each of these four items. Table 3 presents the item content for the GAD10 and PHQ9 items, which showed significant differences between the HT and non-HT groups, and those items that did not show significant differences across HT subgroups.
Discussion The most immediately apparent result from this study of the associations between HT and anxiety and depression is that, although (as expected from the previous literature: [8,9,29]) PCa patients who were currently receiving HT had significantly higher levels of overall anxiety and depression than PCa patients who were not receiving HT, Table 2. Mean (standard deviation) scores in generalised anxiety disorder-10 and Patient Health Questionnaire-9 items across hormone therapy subgroups GAD10 Item Item Item Item Item Item Item Item Item Item Item
No current HT
Current HT
F
p
1 2 3 4 5 6 7 8 9 10 11
1.25 1.13 1.33 1.31 1.20 1.46 1.14 1.68 1.34 1.47 1.28
(.48) (.37) (.56) (.65) (.56) (.67) (.38) (.87) (.64) (.75) (.67)
1.47 (.69) 1.31 (.59) 1.41 (.66) 1.38 (.55) 1.15 (.40) 1.66 (.82) 1.30 (.61) 2.17 (1.00) 1.53 (.73) 1.85 (.91) 1.44 (.77)
5.938 6.022 0.845 0.486 0.304 2.904 4.154 10.444 3.503 8.766 2.292
.016* .015* .358 .487 .582 .090 .043* .002* .063 .004* .132
PHQ9 Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 Item 10
1.16 1.22 1.49 1.57 1.22 1.15 1.24 1.10 1.06 1.22
(.48) (.51) (.78) (.73) (.57) (.49) (.56) (.40) (.29) (.63)
1.38 (.58) 1.46 (.71) 1.90 (.99) 2.14 (.75) 1.42 (.75) 1.22 (.58) 1.38 (.60) 1.15 (.54) 1.07 (.32) 1.30 (.61)
5.995 5.689 8.873 15.986 3.620 0.695 2.335 0.682 0.090 0.734
.015* .018* .004* .000* .059 .406 .129 .410 .765 .393
*p < .05.
Copyright © 2014 John Wiley & Sons, Ltd.
those differences were not uniform across the spectrum of GAD and MDD symptomatologies. While there is no reason to expect that these two HT subgroups would be different on all symptoms of anxiety and depression, that assumption is often made when comparisons between these two subgroups of PCa patients are made on the basis of total scale scores alone. Instead, it appears from these data that, while the overall direct association between HT and total anxiety and depression scores is confirmed by these data, that finding is not as uniform across the diagnostic criteria for GAD and MDD as is suggested by total scale scores. It is when data were examined at the individual GAD and MDD diagnostic criteria level that this paper extended the previous findings on the association between HT and anxiety/depression. PCa patients who were receiving HT had significantly higher GAD10 and PHQ9 scores for the key diagnostic criteria for GAD and MDD, respectively. That is, for GAD, they reported (a) anxiety and (b) difficulty in controlling that anxiety; for MDD, they reported (a) feeling depressed and (b) anhedonia. As such, these key symptom differences argue for the clinical meaningfulness of the differences between the HT subgroups and further support previous research that reported significantly higher anxiety and depression scores in PCa patients who were receiving HT [11,29]. As well as the key diagnostic criteria for GAD and MDD, HT patients also reported fatigue and difficulty sleeping on both the GAD10 and PHQ9, confirming the presence of these symptoms. HT has been associated with fatigue and sleep difficulties in the past, and these findings concur with those pharmacological data [11]. The symptoms that appear in column 4 of Table 3 are of further interest because they show those aspects of GAD and MDD that are not significantly different between HT versus non-HT subgroups. For GAD, these include tension and restlessness, fear, being easily annoyed or irritated and having difficulty with cognitive tasks. For MDD, they include appetite disturbances, poor self concept, psychomotor agitation/retardation and difficulty with cognitive tasks. Put together (as anxiety and depression are comorbid in PCa patients), these findings suggest that the PCa patient who is receiving HT may feel anxious and unable to control that anxiety, sadness, depression and anhedonia, plus tiredness and having difficulties sleeping. The PCa patient who is not receiving HT is more likely to report a wider range of symptoms of GAD and MDD and will be less likely to meet the cutoff for clinically significant anxiety or depression on standardized scales than his or her peer who is receiving HT. However, the finding that, regardless of the difference in GAD and MDD symptomatology between HT and non-HT PCa patients, there was no significant difference in their reported ability to perform their social, work and recreational activities (i.e. the final ‘impairment’ item in each scale) raises some challenge to the seriousness of Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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Table 3. Generalised anxiety disorder-10 and Patient Health Questionnaire-9 items showing significant differences between hormone therapy (HT) and non-HT subgroups (i) GAD10 Item
Significant differences for HT versus non-HT
Item
1 2 7 8 10
Feeling nervous, anxious or on edge Not being able to stop or control my worrying Feeling afraid as if something awful might happen Getting easily tired and worn out Having trouble sleeping
3 4 5 6 9 11
(ii) PHQ9 1 2
Little interest or pleasure in doing usual activities Feeling down, depressed or hopeless
5 6
3 4
Trouble falling asleep or sleeping too much Feeling tired or having little energy
7 8 9 10
the significantly elevated GAD10 and PHQ9 scores in the HT subgroup. That is, while it is unpleasant to experience the symptoms listed in column 2 of Table 3, the HT patients who reported those symptoms did not also indicate that those symptoms interfered with their ability to function across important areas of their lives. Treatment implications from these data are aligned with the move towards precision or personalized medicine that has been recommended during recent years [16,17]. Within that model, the recommendation to assess separate aspects of the overall GAD and MDD symptomatology for treatment planning and delivery now has received further evidential support from the results of this study. In previous decades, there has been a great deal of discussion regarding the benefits/limitations of using standardized or ‘manualized’ treatments for psychological disorders such as anxiety and depression [30,31]. Although the present findings do not negate the content of those manualized approaches per se, they do indicate a need to go further than some simplistic ‘one size fits all’ therapy recommendations, which assume that all anxiety/depression is the same and that the total score from self-report or interview assessment methodologies is the only metric of interest. By contrast, individual PCa patients’ scores on the various symptoms, which comprise GAD and MDD, can be used as particular indicators of the severity of those symptoms, with specific treatment protocols following the patient’s profile on those symptoms. In a recent review of MDD symptomatology, four distinct ‘clinical content’ subtypes of MDD were defined and described, and each was shown to have different underlying neurobiological pathways and treatment needs as well as discrete symptoms [32,33], and these four subtypes of depression have been shown to differ across PCa patients [34]. Those depression subtypes might therefore form a basis on which to assess and Copyright © 2014 John Wiley & Sons, Ltd.
No significant differences for HT versus non-HT Worrying too much about different things Trouble relaxing Being so restless that it is hard to sit still Becoming easily annoyed or irritable Having difficulty concentrating These feelings interfere with my ability to socialize, work or live my life well Poor appetite or overeating Feeling bad about yourself, or that you are a failure, or have let yourself or your family down Trouble concentrating on things, such as reading the newspaper or watching TV Moving or speaking so slowly that other people have noticed. Or being so fidgety or restless that you have been moving around more than usual Thoughts that you would be better off dead or of hurting yourself in some way These feelings interfere with my ability to socialize, work or live my life well
diagnose depression in PCa patients, especially those receiving HT, and to form specific treatment plans on the basis of those diagnoses. A similar process could be undertaken for GAD. There are some limitations to the results of this study, principally those of generalizability. The sample was recruited from only two treatment recruitment sites in one nation, and therefore, further data collection across different recruitment sites and social–cultural environments would be valuable. Although it is a common limitation in studies such as this one, the sample was self-selected, and therefore, the possibility of sample bias must be acknowledged. Further, although the GAD10 and PHQ9 are based upon the diagnostic criteria for GAD and MDD, there may be some differences in results if clinical interviews were used instead of self-report methods. Although participants were categorized according to current HT or not, there may be differences in anxiety and depression according to the type of HT that patients were receiving, such as orally or via injection, and this might also confound treatment compliance. However, despite these common limitations, the specific symptom differences in GAD and MDD symptoms between PCa patients undergoing HT versus those who were not are described here in some detail for the first time. These findings extend previous understanding of how HT is associated with PCa patients’ anxiety and depression and provide the first report on the actual functional impairment effects that these GAD and MDD symptoms had for PCa patients receiving HT. The fact that those effects were minimally different to those in PCa patients who were not receiving HT provides a new challenge for the translation of research findings to clinical settings and urges further detailed examination of the pathways between HT and patients’ mood states. Many Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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PCa patients receive HT, and understanding how that treatment affects them is a key aspect of good psychooncology treatment.
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Conflict of interest The authors have declared no conflicts of interest.
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Psycho-Oncology 23: 1350–1355 (2014) DOI: 10.1002/pon
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