Trajectories of Total Depression and Depressive Symptoms in Prostate Cancer Patients Receiving Six Months of Hormone Therapy

Psycho‐Oncology Psycho‐Oncology (2016) Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/pon.4100

Trajectories of total depression and depressive symptoms in prostate cancer patients receiving six months of hormone therapy

Christopher F. Sharpley1*, David R. H. Christie2, Vicki Bitsika3 and Bradley J. Miller4 1Brain-Behaviour Research Group, University of New England, Armidale, NSW, Australia 2Genesiscare, Tugun, Queensland & Brain-Behaviour Research Group, University of New England, Armidale, NSW, Australia 3Centre for Autism Spectrum Disorders, Bond University, Robina, Queensland, Australia 4Gold Coast University Hospital, Queensland, Australia *Correspondence to: Abstract Brain-Behaviour Research Group, Objective School of Science & Technology, : The aim of this study was to investigate the effects of hormone therapy (HT) on depression University of New England, and depressive symptoms in prostate cancer patients undergoing 6 months of HT. Armidale, NSW, 2351, Australia. Methods: One hundred two prostate cancer patients who had been prescribed HT completed E-mail: [email protected] the Zung Self-rating Depression Scale (SDS) and two questions about their sexual enjoyment and performance, plus a background questionnaire before HT, after 8 to 10 weeks of HT and again after 16 to 20 weeks of HT. Results: There was a significant increase in SDS scores from before to during HT. High depression score before HT was a significant predictor of later increases in depression during HT. Increases in depressive symptoms were restricted to 8 of the 20 SDS symptoms, the most powerful change being in sexual anhedonia, which was a result of decreased ability to perform during sexual activity. Conclusions: The association between HT and elevated depression is confirmed, but the relative influence of sexual anhedonia over other depressive symptoms expands the understanding of this Received: 9 October 2015 association. The effects of decreased ability to perform during sex appear to dominate the increase Revised: 13 December 2015 in depression during HT. Accepted: 19 January 2016 Copyright © 2016 John Wiley & Sons, Ltd.

Background the total scale scores from self-report depression invento- ries, with three exceptions. Lee et al. [10] selected the Although depressed prostate cancer (PCa) patients have somatic symptoms of depression for special attention in increased risk of mortality from all causes [1] and sui- their recent prospective study but did not examine other cide [2], interventions for these PCa patients have been depressive symptoms. Van Dam et al. [12] used six sub- only marginally successful [3]. Some of this variability scales of the Profile of Mood States in their study of the in treatment outcomes may be associated with individ- effects of HT as reported by PCa patients and their part- ual differences in patients’ depressive symptom profiles, ners, but those subscales do not equate to the diagnostic and it may be that better outcomes could follow the symptoms of MDD. Sharpley et al. [9] did examine a application of ‘personalized medicine’ approaches to wider range of depressive symptoms that included those depression [4] that focus upon the depressive symptom- for MDD but did not collect prospective data. Therefore, atology shown by patients [5]. The yardstick for formal to further explore the nature of the depression experienced diagnosis and definition of depression is Major Depres- by PCa patients who received HT, to do so over the period sive Disorder (MDD) [6], which is comprised of nine of their HT instead of at a single point in time, and to thus symptoms. Diagnoses of MDD must include at least inform more individualized treatment practice with these five of these symptoms, including depressed mood or men during their HT, the present study collected data on anhedonia. depression and its symptoms immediately before, after 3 One particular treatment for PCa, which has been asso- months, and after 6 months of HT. Because the depressive ciated with elevated depression, is Hormone Therapy effects of HT have been well established [7–12] and be- (HT). Several cross-sectional and prospective studies of cause this study did not seek to replicate those results the effects of HT have consistently shown that depression but rather to explore the nature of the depressive experi- increases during HT [7–11], allowing this to be accepted ence in HT PCa patients over time, only PCa patients as demonstrated. However, most studies reported only receiving HT were recruited for the study.

Methods interest in sex. Over 80% of male paraplegics continue to experience strong sexual desire [22], indicating that Participants erectile dysfunction does not necessarily lead to sexual Volunteer PCa patients were recruited from a major anhedonia. Because SDS item 6 does not distinguish cancer centre in the Gold Coast, Queensland, during the between failing to enjoy sex because of a lack of period 2008 to 2013. All patients satisfied the criteria of interest/pleasure or because of inability to perform sexual ‘ the American Joint Committee on Cancer Tumor extent, activity, two extra questions were asked: (a) I have expe- ’ lymph Nodes disease spread, Metastatic stage system as rienced a decreased ability to perform during sex and (b) ‘ ’ stage T1-4 N0-1 M0, indicating that the cancer was I have experienced a decreased interest in sex , using the limited to the prostate gland and adjacent lymph nodes. same scoring criteria as for the SDS. All patients had been prescribed a luteinizing hormone- releasing hormone agonist, Leuprorelin Acetate (Eligard Research design ®Tolmar, USA) prior to radiotherapy. Participants completed the first (T1) questionnaires immediately before commencing HT and were posted Materials the questionnaires 3 months later for T2 and another 3 months later for T . Reminder phone calls were used to Demographic information 3 prompt non-returners. All procedures were approved by A background questionnaire was given to participants about the Uniting Care Human Research Ethics Committee, their ages, living situations, and their evaluation of their cur- Brisbane. rent relationships with their wife/partner, children, and other family members and friends, plus their frequency of engag- Statistical analysis ing in exercise. Data regarding time of first diagnosis, present status of their cancer (Gleason score, Prostate Specific Pearson correlations coefficients detected any significant Antigen (PSA)), presence of hot flushes, sexual difficulties relationships between the background variables and SDS and fatigue at T1, plus previous and current treatments were scores. Analysis of variance (ANOVA) and multiple anal- collected from patient records. ysis of variance with repeated measures tested for changes in SDS total scores and individual item scores during the three time points and linear regression were used to deter- Depression mine if any of the background variables were significant The 20-item Zung Self-Rating Depression Scale (SDS) predictors of the change in SDS scores during HT. [13] is based on data from factor analytic studies of MDD [14]. Respondents indicate the frequency of each Results of those 20 items by answering: ‘None of a little of the time’, ‘Some of the time’, ‘Good part of the time’,or Sample characteristics ‘ ’ Most or all of the time , which correspond to numerical Table 1 shows the background, disease and depression scores of 1 to 4, providing total raw scores from 20 to variables for the 102 PCa HT patients recruited for the 80. SDS raw scores of 40 or above indicate the presence ‘ ’ study. All of the SDS scores met the requirements of nor- of clinically significant depression [15, p. 335]. The mality and had non-significant Kolmogorov–Smirnoff SDS has demonstrated split-half reliability of .81 [13], tests. There were no significant relationships between .79 [15], and .94 [16]. Internal consistency (alpha) has SDS total scores at any of the three time points and any been reported as .88 for depressed patients and .93 for of the patients’ background or disease variables. non-depressed patients [17] and as .84 for a previous Australian PCa sample [18]. The SDS has been shown Depression changes over time to be superior to the Minnesota Multiphasic Personality Inventory (MMPI) Depression Scale and the Beck Depres- There was a significant increase in SDS total score over sion Inventory for assessing depression in male psychiatric the three time points (F(2,47) = 9.330, p < .001), and inpatients [17]. Raw scores were used in this study. pairwise comparisons showed that SDS total score at T1 Item 6 of the SDS (I still enjoy sex) measures sexual was significantly lower than at either T2 (p < .001) or T3 anhedonia that is reported by some PCa patients following (p < .001) but that there was no significant difference treatment [19]. Sexual anhedonia may arise from a range between SDS total scores at T2 and T3. The differences of causes such as age [20] and has also been reported in in SDS total score from T1 to T2 and T3 may also be up to 50% of healthy men, due to stress [21]. Erectile calculated as a unique variable by subtracting the SDS dysfunction may occur in a proportion of PCa patients T1 total score from the SDS T2 total score. Background but negative responses to SDS item 6 do not necessarily and disease variables at each of the three time points were solely reflect that and could instead be due to loss of entered into a separate linear regression on this change in

Table 1. Background and disease data and SDS scores at three time points Variable HT Patients (n = 102)

Age M = 71.78 years (SD = 5.12 years) Range = 53 to 83 years Time since diagnosis M = 23.46 weeks (SD = 61.34 weeks) Previous treatments for PCa N Percent Surgery 5 4.9 Radiation therapy 1 0.9 Chemotherapy 0 0.0 Hormone therapy 0 0.0 Gleason score M = 7.47 (SD = 0.82)

PSA at T1 M = 11.95 (SD =7.15) PSA at T2 M = 5.61 (SD = 3.76)

PSA at T3 M = 1.17 (SD = 1.43) Presence of sexual difﬁculties M = 0.0 Depression variable T1 T2 T3 SDS Total score 31.41 (7.99) 35.56 (7.32) 35.33 (7.88) SDS Depressed mood 4.16 (1.38) 4.17 (1.27) 4.19 (1.57) SDS Anhedonia 6.37 (2.63) 7.06 (2.18) 7.18 (2.12)

SDS, Zung Self-rating Depression Scale; HT, hormone therapy; PCa, prostate cancer; SD, standard deviation.

SDS total score from T1 to T2, but there were no signifi- items 4, 6, and 8 are from that source. Values for the cant effects. SDS total score at T1 was a significant predic- remaining SDS items are based on non-violation of tor of both SDS total score at T2 (Standardized sphericity. Beta = .458, t = 2.817, p < .01) and the change in SDS total The statistically significant changes between time score from T1 to T2 (Standardized Beta = .661, t = 4.566, points are shown in bold text in the last three columns of p < .001). Using the method for identifying ‘clinically Table 2, indicating that only SDS items 6 and 13 were significant’ depression on the SDS by reference to a raw immediately influenced by HT during the first 3 months score of 40 or more [23], 17.3% of these patients met that of administration (i.e., from T1 to T2) and that SDS items criterion at T1, 25.7% at T2, and 28.6% at T3, reflecting 4, 8, and 10 showed significant increases only between T1 the ANOVA results that the major change in depression to T3. As such, patients’ sexual anhedonia and restlessness occurred during the first 3 months of HT. appeared to be the most sensitive (in terms of time) to HT, while sleeping difficulties, constipation, and fatigue were only affected by longer periods of HT. Although there Zung self-rating depression scale items was a significant overall effect in patients’ irritability Multiple analysis of variance with repeated measures during HT, that change was not associated with either on the 20 SDS items produced a significant main effect the first or second three-month period of HT. Overall, it (F(40,17) = 2.698, p = .015 (Wilks Lambda), partial eta was the patients’ sexual anhedonia that was most power- square = .864), which is a very large effect [24]. There fully influenced by HT, with an effect size approximately were significant univariate effects for SDS items 4, 6, two and a half times that for each of the remaining SDS 8, 10, 13, and 15, and the means (SD) and statistical items (Table 2). None of the background or disease vari- results for those items are shown in Table 2. Scores ables were significant predictors of change in patients’ on items 4, 6, and 8 violated the assumption of sphe- SDS item 6 scores from T1 to T2 or from T1 to T3. The ricity, but Mauchly’s W was > .75, justifying the relative influence of sexual anhedonia on patients’ overall Huynh–Feldtcorrectiontotheseresults[25]andresults depression was confirmed by another ANOVA with of the univariate tests presented in Table 2 for SDS repeated measures on SDS total scores from T1 to T2

Table 2. Univariate effects and post-hoc comparisons for SDS items with signiﬁcant change during the HT period

SDS item M (SD) T1 M (SD) T2 M (SD) T3 FpPartial eta square T1 vs T2 p T2 vs T3 p T1 vs T3 p

4. I have trouble sleeping at night 1.578 (0.754) 1.859 (0.811) 1.824 (0.804 4.392 .019 .073 .067 1.000 .010 6. I still enjoy sex (reverse scored) 2.877 (1.350) 3.543 (0.887) 3.631 (0.937) 11.906 < .001 .175 .001 1.000 .001 8. I have trouble with constipation 1.245 (0.509) 1.368 (0.522) 1.473 (0.758) 3.393 .043 .051 .269 .879 .043 10. I get tired for no reason 1.561 (0.627 1.754 (0.662) 1.894 (0.838) 4.311 .016 .071 .281 .693 .014 13. I am restless and cannot keep still 1.403 (0.622) 1.667 (0.932) 1.526 (0.709) 4.253 .017 .071 .013 .517 .383 15. I am more irritable than usual 1.386 (0.619) 1.578 (0.680) 1.614 (0.725) 3.204 .037 .057 .061 1.000 .080

SDS, Zung Self-rating Depression Scale; HT, hormone therapy; SD, standard deviation.

Clinically signiﬁcant sexual anhedonia

If the same basis for identifying clinically significant depression based on the total SDS score (i.e., a raw score of 40 or more out of a possible score of 80, equating to a symptom being present ‘A good part of the time’ [13]) was applied to the SDS items shown in Table 2, then a raw score of 2 or above (out of a possible score of 4) for each item could be used to identify those patients whose SDS item scores corresponded to this severity indicator of clinically significance. From Table 2, only SDS item 6 had a mean score at T2 or T3 that fell into this clinically Figure 1. Mean inability to perform during sex versus loss of inter- significant category. However, the mean score for SDS est in sex scores (plus 0.5 SD error bars) across three time points of hormone therapy item 6 at T1 also fell into this category, indicating that many of these men were experiencing sexual anhedonia prior to receiving HT. and T3 without item 6 included in that total score. Unlike Therefore, it is of interest to determine the actual nature the result reported above for the entire 20-item SDS, there of the sexual anhedonia experienced by these men (i.e., if was no significant effect due to time (F(2,61) = 0.636, it was due to a reduction in sexual activity, sexual enjoy- p = .533) when sexual anhedonia was removed from the ment, or both). Figure 1 presents the mean scores (plus SDS score. 0.5 SD error bars) over T1 to T3 for the two extra items

Figure 2. (a) Change in Inability to perform during sex during hormone therapy patients classiﬁed according to their scores on ‘Decreased ability to perform during sex’ at T1; (b) Change in Interest in sex during hormone therapy patients classiﬁed according to their scores on ‘Decreased ability to perform during sex’ at T1

described earlier (i.e., loss of interest in sex, loss of ability Conclusions to perform during sex). As for the SDS, higher scores are indicative of more frequent/severe responses. Pairwise Although the overall SDS total scores confirmed findings comparisons showed that frequency of being unable to from several previous cross-sectional and prospective perform during sex significantly increased from T1 to T2 studies that depression significantly increased during (p < .001) and T1 to T3 (p < .001) but that there was no HT, drilling down into these data and examining two fur- significant difference between scores at T2 and T3. The ther aspects of their sexual performance/interest indicated mean score for being unable to perform during sex was that the significant depressive effect of HT was principally 2.18 at T1, reflecting a frequency of ‘Some of the time’, due to increases in sexual anhedonia that were a result of and this rose above 3.0 (‘A good part of the time’)atT2 decreased ability to perform during sex rather than loss and T3. There were no significant correlations between of interest in sex. Further, those performance-linked scores on this measure of sexual performance and age, increases in sexual anhedonia were most acutely felt by time since diagnosis, Gleason scores, PSA or any of those men who had not experienced those problems previ- the other family relationship, or activity factors mea- ously compared with those men who had existing loss of sured in the background questionnaire. There was no ability to perform during sex before receiving HT. That significant change in patients’ interest in sex, suggesting is, the latter men did not actually lose any sexual ability that the significant increase in sexual anhedonia reported during HT, but those men who were sexually capable earlier was largely due to their inability to perform prior to HT did lose their ability to perform, and it made during sex. them depressed. This loss of ability to perform during To identify which patients experienced this decrease in sex was significantly associated with elevated SDS total ability to perform during sex, patients were identified scores. according to their T1 score for the question and classified It is of interest that the analysis of the 20 SDS items according to that score (i.e., 1 = None or a little of the time, identified that it was sexual anhedonia rather than 2 = Some of the time, 3 = Good part of the time, and depressed mood, which was significantly increased during 4 = Most or all of the time). From these classifications, HT, but that more general anhedonia measured by the their changes in ability to perform during sex and their SDS items ‘I still enjoy doing the things I used to do’ interest in sex were plotted (Figure 2a). It is apparent that and ‘My life is pretty full’ did not change significantly the largest increases in inability to perform during sex during HT. These findings reveal a degree of detail not were for those patients who reported no such decrease in previously reported about the ways in which these men ability before HT (i.e., a score of ‘None’). These men became depressed during HT and argue that the overall had large increases in their inability to perform during depression that PCa patients experience during HT might sex from T1 to T2 but lesser increases from T2 to T3.A be most likely to be related to their HT-induced reduction similar effect was noted for those patients who reported in sexual performance. Although it was not measured in having a decrease in their ability to perform during sex this study, it is likely that this reduction in performance only ‘Some of the time’ prior to HT. By contrast, those refers to a lack of either getting or maintaining an erec- patients who had experienced a decrease in their ability tion, which is a direct outcome of lowered testosterone to perform during sex ‘A good part of the time’ or ‘Most and to be expected in patients undergoing testosterone- or all of the time’ before HT showed very little change reducing HT. in their ability to perform during sex. When the interest Previous data reporting a significant increase in depres- that these patients had in sex was examined (Figure 2b), sion during HT are not challenged by the current findings. there were only very minor changes for any of these four Instead, these data extend those findings to identification subgroups of patients, indicating that HT did not have of the actual nature of those depressive symptomatology much of an influence on that aspect of their sexual score increases and are congruent with them. Lee et al. anhedonia. [10] questioned whether the increases in CESD scores The effect of this pre-HT ability to perform during sex during HT might be a result of decreased testosterone, in- upon SDS total scores was examined by categorizing creases in HT side effects such as sarcopenia, hot flashes patients into those who had T1 scores of ‘None’ or ‘Some or cognitive difficulties, or other changes associated with of the time’ versus those who had T1 scores of ‘Good part HT, and van Dam et al. [12] noted significant decreases of the time’ or ‘Most of the time’ for inability to perform in Vigor on the POMS during HT. The results of this during sex. Although there was no significant difference study do not address that entire range of possible sources in their SDS total scores before HT at T1 (F(1,85) of increased depression but do argue that it was majorly = 0.119, p = .731), the SDS total scores for the former sexual anhedonia that was responsible for increases in subgroup (M = 6.86) were significantly lower than those overall depression during HT. for the latter subgroup (M = 7.51: F = 4.583, p = .036. These findings argue strongly for the relevance of the partial eta square = .062) at T2. treatment approaches that have been shown to be effective

with anhedonia (i.e., pharmacology) rather than those used by studies in which these data are collected more fre- with success for depressed mood (psychotherapies), quently. Although one previous study [28] found that although the side effects of antidepressant medication PCa patients with previous history of depression were can also include loss of libido [26]. However, going more likely to become depressed during HT, those data further than that, it may be that the feelings of loss that regarding previous history were obtained from clinical these men experienced during HT as a result of their interviews at the time of the study rather than from actual inability to perform during sex might be targeted for medical records, and this finding applied to only five of 45 therapies that (a) challenge their beliefs that erections are PCa patients (11.1% of the sample), suggesting that the necessary for satisfactory sexual activity, (b) teach them association between previous history of depression and alternative sources of sexual satisfaction and activity and the likelihood of becoming depressed during HT needs (c) provide pharmacotherapy interventions that may further investigation. Further, the SDS measured fatigue enhance the erectile function of those men who lose that via a single item and further exploration of the multifac- during HT. For example, it has previously been reported torial nature of fatigue might provide a greater under- that 85% of PCa patients with erectile dysfunction were standing of this association, as would inclusion of other successfully treated with sildenafil citrate [27], although medical conditions that might influence depression and the restriction of patients to those who received radiation fatigue, such as anemia. Finally, patients in this study therapy limits the generalisability of those findings. Over received Leuprorelin Acetate (Eligard®, Tolmar, USA), 80% of male paraplegics continue to experience strong and no generalization is made to the effects of other sexual desire [22] despite having no ability to obtain an forms of HT. erection without biomechanical intervention. Psychother- Overall, the findings of this study add to those previ- apy might be of assistance in helping these men to accept ously reported regarding the depressogenic effects of that (temporary) decrease in erectile performance do not HT by describing the powerful role that sexual anhedonia necessarily lead to depression and that other sources of induced by inability to perform during sex had upon receiving and giving sexual pleasure might be reasonably these men’s depressive status. Although there is a clear substituted for penile erection while the effects of HT are association between HT and elevated depression (most present. likely for those who commenced HT with already The results of this study are limited by the range of elevated depression), the presence of HT-related failure biological and psychosocial factors that were measured. to perform during sex appears to be a major factor in their The sample was drawn from a local site in Queensland, depression. Australia, and generalisability to other cultures and nations is limited. Depression was assessed at only three points during HT, and definition of more precisely when Acknowledgements (within the first three months of HT) depression (and sex- This study was supported by a Project Grant from Hospira P/L ual anhedonia) first begins to increase could be provided (Australia).

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