- Email: [email protected]
Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition
EUF-842; No. of Pages 3 E U RO P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Mini Review – Prostate Cancer
Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition Jason P. Izard a,b,c,*, D. Robert Siemens a,b,c a
Department of Urology, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Queen’s University, Kingston, Canada;
b
Department of Oncology, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Queen’s University, Kingston, Canada;
c
Queen’s University Cancer Research Institute, Queen’s University, Kingston, Canada
Article info
Abstract
Article history: Accepted November 25, 2019
Androgen deprivation therapy (ADT) is a common treatment for many men with prostate cancer. Use of ADT can have significant impacts on the mental health of patients with both localized and advanced disease. Prostate cancer patients receiving ADT have a 41% higher risk of depression and a 47% higher risk of dementia. Risk factors for the development of depression in this group of men include older age, marital status, greater comorbidity, and a previous history of depression, while being retired may offer a protective effect. Optimal treatment strategies for depression for these men are not well established in the literature. Patient summary: We reviewed the association between androgen deprivation therapy (ADT) use by men with prostate cancer and the risk of mental health issues. There appears to be a higher risk of both depression and cognitive impairment for men receiving ADT. Optimal treatments for depression for men on ADT are still not well studied. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Derya Tilki Keywords: Androgen Deprivation Therapy Depression Mental Health Cognition
* Corresponding author. Victory 4, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada. Tel.: +1 613 5482493, Fax: +1 613 5451970. E-mail address: [email protected] (J.P. Izard).
Androgen deprivation therapy (ADT) is a mainstay of treatment for many men with prostate cancer. Data from Surveillance, Epidemiology and End Results (SEER)Medicare estimate that approximately 45% of men diagnosed with prostate cancer will be exposed to ADT within 1 yr of their diagnosis [1]. Given the large volume of men diagnosed with prostate cancer each year, the prevalence of ADT use within the population is estimated to be approximately 3% at any given time. ADT use is not without adverse effects and is associated with changes in numerous aspects of overall health, including cardiovascular health, muscle mass, fat composition, bone health, insulin sensitivity,
libido, erections, and numerous domains for health-related quality-of-life measures [2]. Despite the reality that ADT is often used for more advanced disease, most prostate cancers patients starting ADT are still expected to have a survival time measured in years, and strategies to promote wellbeing are crucial. There has recently been increasing recognition of the impact of ADT on mental health among patients with prostate cancer. Among male patients without prostate cancer, low testosterone and hypogonadal states have been linked to depressive symptoms that can improve with supplementation of testosterone levels [3]. There is some
https://doi.org/10.1016/j.euf.2019.11.010 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Izard JP, Siemens DR, Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2019.11.010
EUF-842; No. of Pages 3 2
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
evidence of an underlying biologic basis to depressive symptoms that is related to hypogonadism. Polymorphisms affecting the length of the CAG repeat sequence in the N-terminal transactivation domain of the androgen receptor may play a role in some cases of depression in men without prostate cancer [4]. It stands to reason that ablation of testosterone in prostate cancer patients could induce a similar constellation of depressive symptoms that unfortunately are not easily reversible with testosterone supplementation owing to the nature of the disease. In addition, not all patients recover their testosterone levels after finishing ADT and their hypogonadal state may persist. Clinical depression is, of course, not easily attributable to one root cause. Multiple factors influence the risk of depression among men receiving ADT, including age, marital status, retirement status, number of comorbidities, and a previous history of depression [5,6]. Situational and psychological factors may be more impactful than biological factors on a prostate cancer patient’s psychological wellbeing. ADT may further disrupt this complex balance by altering body image, affecting libido and erections, and thereby complicating partner relations for this group of men [7]. The distress that these effects have on the partner may further exacerbate this complex interplay of factors. Some studies have shown that the psychological distress experienced by the partner of a prostate cancer patient may be as high as or higher than that of the patient [8]. Superficially, one might also conclude that the use of ADT simply serves as a surrogate marker for more advanced disease. Therefore, depressive symptoms might be ascribed to the poor prognosis of the disease and not the therapeutic intervention. However, when examining men with localized prostate cancer within SEER-Medicare, use of ADT was associated with a 23% higher risk of depression and a 29% higher risk of inpatient psychiatric services [6]. The cumulative incidence of depression increased with ADT duration, suggesting a dose-response relationship that was not mitigated when the authors adjusted for clinical and demographic variables. Furthermore, a meta-analysis of studies including patients with both localized and advanced disease found that ADT use conferred a 41% higher risk of depression [9]. This risk appeared even stronger when limiting the analysis to patients with localized disease, thereby likely refuting the claim that this phenomenon is simply reflective of worse disease. Cognitive impairment has been linked to depression and it is unclear what exact connection each of these entities plays in the development of the other among patients on ADT. There are androgen receptors in the brain and it is not surprising that withdrawal of testosterone has been linked to changes in verbal memory, visuospatial ability, and executive functions. A recent systematic review of the literature on cognitive effects in ADT found substantial variation in the rates reported and the magnitudes of effects because of heterogeneity in the definitions and measurement tools used [10]. The length of follow-up for all studies was limited and varied, with no study having longer than 12 mo of follow-up. Nonetheless, several of the studies did indicate that a reduction in cognition can appear as early as 3 mo
after initiation of ADT. The downstream effects of this impairment may be very clinically significant, as a systematic review involving 50 541 individuals suggests a 47% increase in the risk of dementia among patients receiving ADT [11]. Studies specifically assessing treatment regimens for depression in prostate cancer patients currently receiving or who have received ADT are lacking. Of course, judicious use of ADT would intrinsically make sense as a preventative strategy. Intermittent as opposed to continuous ADT use has been advocated for mitigation of some of the potential side effects of treatment. Nevertheless, the effect of intermittent ADT on depressive symptoms does not appear to be substantially different to that of continuous ADT [9]. Studies on physical exercise programs for men on ADT have yielded promising results with respect to depression outcomes; however, the results are confounded by high dropout rates for the intervention [12]. Epidemiological studies have shown that approximately 14% of men on ADT have received prescriptions for antidepressant medications, but the comparative efficacy of that treatment is not known [13]. The American Society of Clinical Oncology has endorsed the Canadian Association of Psychosocial Oncology and Canadian Partnership Against Cancer guideline recommending that all patients with cancer and cancer survivors be evaluated for symptoms of depression and anxiety at baseline and at periodic times using validated instruments [14]. They have published suggested treatment algorithms based on depression severity; however, these treatment guidelines are not specific for prostate cancer patients and have not been validated in a population of men specifically receiving ADT. Although ADT represents a mainstay of treatment in men with both localized and metastatic prostate cancer, the magnitude of psychological effects of the treatment appears to extend beyond what we could reasonably ascribe to the psychological distress of a cancer diagnosis. Timely recognition of these effects is important as they can appear early on in treatment and have significant impacts on the quality of life of both the patient and his partner. More studies are required to identify the optimal treatment strategies for the mental health needs of men receiving ADT. Conflicts of interest: The authors have nothing to disclose.
References [1] Gilbert SM, Kuo YF, Shahinian VB. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States. Urol Oncol 2011;29:647–53. [2] Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003;61:32–8. [3] Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract 2009;15:289–305. [4] Harkonen K, Huhtaniemi I, Makinen J, et al. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men. Int J Androl 2003;26:187–94.
Please cite this article in press as: Izard JP, Siemens DR, Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2019.11.010
EUF-842; No. of Pages 3 3
E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
[5] Fervaha G, Izard J, Tripp D, et al. Depression in prostate cancer patients starting androgen deprivation therapy. J Urol 2019;201:e322. [6] Dinh KT, Reznor G, Muralidhar V, et al. Association of androgen deprivation therapy with depression in localized prostate cancer. J Clin Oncol 2016;34:1905–12.
[11] Nead KT, Sinha S, Nguyen PL. Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis. Prostate Cancer Prostat Dis 2017;20: ]259–64. [12] Culos-Reed SN, Robinson JW, Lau H, et al. Physical activity for
[7] Benedict C, Traeger L, Dahn JR, et al. Sexual bother in men with
men receiving androgen deprivation therapy for prostate can-
advanced prostate cancer undergoing androgen deprivation ther-
cer: benefits from a 16-week intervention. Support Care Cancer
apy. J Sex Med 2014;11:2571–80. [8] Kornblith AB, Herr HW, Ofman US, Scher HI, Holland JC. Quality of
2010;18:591–9. [13] Bill-Axelson A, Garmo H, Nyberg U, et al. Psychiatric treatment in
life of patients with prostate cancer and their spouses. The value of a
men with prostate cancer—results from a nationwide, population-
data base in clinical care. Cancer 1994;73:2791–802.
based
[9] Nead KT, Sinha S, Yang DD, Nguyen PL. Association of androgen deprivation therapy and depression in the treatment of prostate cancer: a systematic review and meta-analysis. Urol Oncol 2017;35, 664.e1–9. [10] Treanor CJ, Li J, Donnelly M. Cognitive impairment among prostate cancer patients: an overview of reviews. Eur J Cancer Care 2017;26:e12642.
cohort
study
from
PCBaSe
Sweden.
Eur
J
Cancer
2011;47:2195–201. [14] Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol 2014;32:1605–19.
Please cite this article in press as: Izard JP, Siemens DR, Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2019.11.010
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Mini Review – Prostate Cancer
Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition Jason P. Izard a,b,c,*, D. Robert Siemens a,b,c a
Department of Urology, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Queen’s University, Kingston, Canada;
b
Department of Oncology, Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Queen’s University, Kingston, Canada;
c
Queen’s University Cancer Research Institute, Queen’s University, Kingston, Canada
Article info
Abstract
Article history: Accepted November 25, 2019
Androgen deprivation therapy (ADT) is a common treatment for many men with prostate cancer. Use of ADT can have significant impacts on the mental health of patients with both localized and advanced disease. Prostate cancer patients receiving ADT have a 41% higher risk of depression and a 47% higher risk of dementia. Risk factors for the development of depression in this group of men include older age, marital status, greater comorbidity, and a previous history of depression, while being retired may offer a protective effect. Optimal treatment strategies for depression for these men are not well established in the literature. Patient summary: We reviewed the association between androgen deprivation therapy (ADT) use by men with prostate cancer and the risk of mental health issues. There appears to be a higher risk of both depression and cognitive impairment for men receiving ADT. Optimal treatments for depression for men on ADT are still not well studied. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Derya Tilki Keywords: Androgen Deprivation Therapy Depression Mental Health Cognition
* Corresponding author. Victory 4, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada. Tel.: +1 613 5482493, Fax: +1 613 5451970. E-mail address: [email protected] (J.P. Izard).
Androgen deprivation therapy (ADT) is a mainstay of treatment for many men with prostate cancer. Data from Surveillance, Epidemiology and End Results (SEER)Medicare estimate that approximately 45% of men diagnosed with prostate cancer will be exposed to ADT within 1 yr of their diagnosis [1]. Given the large volume of men diagnosed with prostate cancer each year, the prevalence of ADT use within the population is estimated to be approximately 3% at any given time. ADT use is not without adverse effects and is associated with changes in numerous aspects of overall health, including cardiovascular health, muscle mass, fat composition, bone health, insulin sensitivity,
libido, erections, and numerous domains for health-related quality-of-life measures [2]. Despite the reality that ADT is often used for more advanced disease, most prostate cancers patients starting ADT are still expected to have a survival time measured in years, and strategies to promote wellbeing are crucial. There has recently been increasing recognition of the impact of ADT on mental health among patients with prostate cancer. Among male patients without prostate cancer, low testosterone and hypogonadal states have been linked to depressive symptoms that can improve with supplementation of testosterone levels [3]. There is some
https://doi.org/10.1016/j.euf.2019.11.010 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Izard JP, Siemens DR, Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2019.11.010
EUF-842; No. of Pages 3 2
E U RO P E A N U RO L O GY F O C U S X X X ( 2 019 ) X X X– X X X
evidence of an underlying biologic basis to depressive symptoms that is related to hypogonadism. Polymorphisms affecting the length of the CAG repeat sequence in the N-terminal transactivation domain of the androgen receptor may play a role in some cases of depression in men without prostate cancer [4]. It stands to reason that ablation of testosterone in prostate cancer patients could induce a similar constellation of depressive symptoms that unfortunately are not easily reversible with testosterone supplementation owing to the nature of the disease. In addition, not all patients recover their testosterone levels after finishing ADT and their hypogonadal state may persist. Clinical depression is, of course, not easily attributable to one root cause. Multiple factors influence the risk of depression among men receiving ADT, including age, marital status, retirement status, number of comorbidities, and a previous history of depression [5,6]. Situational and psychological factors may be more impactful than biological factors on a prostate cancer patient’s psychological wellbeing. ADT may further disrupt this complex balance by altering body image, affecting libido and erections, and thereby complicating partner relations for this group of men [7]. The distress that these effects have on the partner may further exacerbate this complex interplay of factors. Some studies have shown that the psychological distress experienced by the partner of a prostate cancer patient may be as high as or higher than that of the patient [8]. Superficially, one might also conclude that the use of ADT simply serves as a surrogate marker for more advanced disease. Therefore, depressive symptoms might be ascribed to the poor prognosis of the disease and not the therapeutic intervention. However, when examining men with localized prostate cancer within SEER-Medicare, use of ADT was associated with a 23% higher risk of depression and a 29% higher risk of inpatient psychiatric services [6]. The cumulative incidence of depression increased with ADT duration, suggesting a dose-response relationship that was not mitigated when the authors adjusted for clinical and demographic variables. Furthermore, a meta-analysis of studies including patients with both localized and advanced disease found that ADT use conferred a 41% higher risk of depression [9]. This risk appeared even stronger when limiting the analysis to patients with localized disease, thereby likely refuting the claim that this phenomenon is simply reflective of worse disease. Cognitive impairment has been linked to depression and it is unclear what exact connection each of these entities plays in the development of the other among patients on ADT. There are androgen receptors in the brain and it is not surprising that withdrawal of testosterone has been linked to changes in verbal memory, visuospatial ability, and executive functions. A recent systematic review of the literature on cognitive effects in ADT found substantial variation in the rates reported and the magnitudes of effects because of heterogeneity in the definitions and measurement tools used [10]. The length of follow-up for all studies was limited and varied, with no study having longer than 12 mo of follow-up. Nonetheless, several of the studies did indicate that a reduction in cognition can appear as early as 3 mo
after initiation of ADT. The downstream effects of this impairment may be very clinically significant, as a systematic review involving 50 541 individuals suggests a 47% increase in the risk of dementia among patients receiving ADT [11]. Studies specifically assessing treatment regimens for depression in prostate cancer patients currently receiving or who have received ADT are lacking. Of course, judicious use of ADT would intrinsically make sense as a preventative strategy. Intermittent as opposed to continuous ADT use has been advocated for mitigation of some of the potential side effects of treatment. Nevertheless, the effect of intermittent ADT on depressive symptoms does not appear to be substantially different to that of continuous ADT [9]. Studies on physical exercise programs for men on ADT have yielded promising results with respect to depression outcomes; however, the results are confounded by high dropout rates for the intervention [12]. Epidemiological studies have shown that approximately 14% of men on ADT have received prescriptions for antidepressant medications, but the comparative efficacy of that treatment is not known [13]. The American Society of Clinical Oncology has endorsed the Canadian Association of Psychosocial Oncology and Canadian Partnership Against Cancer guideline recommending that all patients with cancer and cancer survivors be evaluated for symptoms of depression and anxiety at baseline and at periodic times using validated instruments [14]. They have published suggested treatment algorithms based on depression severity; however, these treatment guidelines are not specific for prostate cancer patients and have not been validated in a population of men specifically receiving ADT. Although ADT represents a mainstay of treatment in men with both localized and metastatic prostate cancer, the magnitude of psychological effects of the treatment appears to extend beyond what we could reasonably ascribe to the psychological distress of a cancer diagnosis. Timely recognition of these effects is important as they can appear early on in treatment and have significant impacts on the quality of life of both the patient and his partner. More studies are required to identify the optimal treatment strategies for the mental health needs of men receiving ADT. Conflicts of interest: The authors have nothing to disclose.
References [1] Gilbert SM, Kuo YF, Shahinian VB. Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States. Urol Oncol 2011;29:647–53. [2] Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Urology 2003;61:32–8. [3] Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract 2009;15:289–305. [4] Harkonen K, Huhtaniemi I, Makinen J, et al. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men. Int J Androl 2003;26:187–94.
Please cite this article in press as: Izard JP, Siemens DR, Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2019.11.010
EUF-842; No. of Pages 3 3
E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
[5] Fervaha G, Izard J, Tripp D, et al. Depression in prostate cancer patients starting androgen deprivation therapy. J Urol 2019;201:e322. [6] Dinh KT, Reznor G, Muralidhar V, et al. Association of androgen deprivation therapy with depression in localized prostate cancer. J Clin Oncol 2016;34:1905–12.
[11] Nead KT, Sinha S, Nguyen PL. Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis. Prostate Cancer Prostat Dis 2017;20: ]259–64. [12] Culos-Reed SN, Robinson JW, Lau H, et al. Physical activity for
[7] Benedict C, Traeger L, Dahn JR, et al. Sexual bother in men with
men receiving androgen deprivation therapy for prostate can-
advanced prostate cancer undergoing androgen deprivation ther-
cer: benefits from a 16-week intervention. Support Care Cancer
apy. J Sex Med 2014;11:2571–80. [8] Kornblith AB, Herr HW, Ofman US, Scher HI, Holland JC. Quality of
2010;18:591–9. [13] Bill-Axelson A, Garmo H, Nyberg U, et al. Psychiatric treatment in
life of patients with prostate cancer and their spouses. The value of a
men with prostate cancer—results from a nationwide, population-
data base in clinical care. Cancer 1994;73:2791–802.
based
[9] Nead KT, Sinha S, Yang DD, Nguyen PL. Association of androgen deprivation therapy and depression in the treatment of prostate cancer: a systematic review and meta-analysis. Urol Oncol 2017;35, 664.e1–9. [10] Treanor CJ, Li J, Donnelly M. Cognitive impairment among prostate cancer patients: an overview of reviews. Eur J Cancer Care 2017;26:e12642.
cohort
study
from
PCBaSe
Sweden.
Eur
J
Cancer
2011;47:2195–201. [14] Andersen BL, DeRubeis RJ, Berman BS, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol 2014;32:1605–19.
Please cite this article in press as: Izard JP, Siemens DR, Androgen Deprivation Therapy and Mental Health: Impact on Depression and Cognition. Eur Urol Focus (2020), https://doi.org/10.1016/j.euf.2019.11.010