Neuropsychiatric effects of ADT often overlooked

Badar M. Mian, MD

In “Journal Article of the Month," Badar M. Mian, MD, offers perspective on noteworthy research in the peer-reviewed literature. Dr. Mian is professor of surgery in the division of urology at Albany Medical College, New York.

Although the physiologic adverse effects of androgen-deprivation therapy (ADT), such as hot flashes, fatigue, osteoporosis, and sexual dysfunction, are regularly discussed with patients, the neurocognitive complications (such as depression, cognitive decline, and dementia) are often overlooked. Despite the reportedly strong association between ADT for prostate cancer and several psychological adverse effects, clinical guidelines to address these issues are lacking. Recently, Siebert et al performed a systematic review of the literature to demonstrate the strength of existing data and to offer recommendations regarding identification and management of neuropsychiatric adverse effects of ADT.¹

The authors summarized the findings from 48 articles outlining the current evidence for neuropsychiatric consequences of ADT and proposed interventions. They also performed 2 meta-analyses examining the risk of depression and dementia after initiating ADT. The data from prospective, controlled studies demonstrate a causal relationship between ADT initiation and incidence of clinical depression. Results suggest that ADT initiation not only worsens pre-existing depression (in as early as 1 month), but may also trigger the development of clinical depression after approximately 1 year on treatment.

A study of patients in the Danish Prostate Cancer Registry showed an association between ADT and depression (HR, 1.8; P <.001) after adjustment for comorbidities. Their data suggest that ADT exposure is a risk factor for the development of depression, especially when used with concurrent radiation therapy. Meta-analysis of studies in this report demonstrates 1.51 times (P = .0002) increased risk of incident depression after ADT exposure.

A dose-dependent relationship between the duration of ADT and depressive symptoms has been demonstrated in several studies. Among prostate cancer patients in the TRICARE military database (n = 9117), ADT was associated with a higher incidence of depression (HR, 2.07; P <.001), which worsened with the duration of therapy. This dose-response relationship between ADT and depression has also been demonstrated in Chinese and Australian populations. Cumulatively, these data demonstrate significant risk of incident depression and worsening symptoms in men with depressive disorder after initiating ADT.

The data on ADT-related cognitive impairment can vary, depending upon the study population and methodology used to measure the outcome. ADT, compared with healthy controls, was associated with decreased short-term memory and working memory (P <.02). A prospective study of men starting ADT compared with matched individuals undergoing prostatectomy showed higher rates of cognitive impairment at 6 and 12 months. Similarly, men initiating ADT (vs prostatectomy) had a negative impact on language ability and short-term memory capacity (P <.05). These findings suggest an association between ADT and cognitive impairment such as memory loss can be detected as early as 6 months after initiating ADT.

Several large, American studies have demonstrated a consistent association between ADT and subsequent development of Alzheimer dementia (AD). As compared with non-ADT prostate cancer controls, men receiving ADT were at increased risk of AD (HR, 1.14; P <.001) and all-cause dementia (HR, 1.20; P <.001), dependent upon the duration of ADT. A study of men in the SEER-Medicare database found that those receiving ADT were 20% more likely to develop AD, after controlling for race, ethnicity, prostate cancer stage, and comorbidities.

Another analysis of SEER data of men receiving ADT demonstrated a dose-dependent increased risk of all-cause dementia and AD at 22% and 29%, respectively. ADT exposure for at least 7 months was associated with a 41% increase in all-cause dementia and 30% increased risk of AD compared with prostate cancer controls without ADT. Meta-analysis of several non-American population data sets showed approximately 1.45 times (P = .02) increased risk of all-cause dementia after ADT exposure.

The authors recommend brief baseline affect and cognitive screening assessments in all patients initiating ADT, particularly those with prior diagnosis or treatment for depression or cognitive impairment. One of the challenges in identifying neurocognitive dysfunction in men receiving ADT is that several of the symptoms overlap with the symptoms of hypogonadism (such as fatigue, lack of desire, and decreased mental sharpness). The authors recommend that all patients starting long-term ADT be counseled regarding possible neuropsychiatric adverse effects, and provided some information about the connection between ADT and mental health. Knowledge of these potential adverse effects can reduce the negative psychological impact or stigma associated with discussion of mental health issues.

Although urologists are quite adept at identifying and addressing the links between urologic conditions/treatments and non-urologic conditions (erectile dysfunction and coronary disease; ADT and osteoporosis), discussion about mental health are often omitted. In any patient receiving ADT for more than 6 months, a patient-administered assessment tool, the Patient Health Questionnaire-9, can be used to screen for depressive disorder. A simple query by the providers, such as “have you been feeling down,” can open the door to acknowledging mental health issues, facilitating a discussion or referral to a mental health professional. As the primary care physicians for prostate cancer, and the main prescribers of ADT, we, the urologists, owe it to our patients to address both the physiologic and the neuropsychiatric adverse effects.

Reference

1. Siebert AL, Lapping-Carr L, Morgans AK. Neuropsychiatric impact of androgen deprivation therapy in patients with prostate cancer: current evidence and recommendations for the clinician. Eur Urol Focus. Published online July 17, 2020. S2405-4569(20)30149-8. doi:10.1016/j.euf.2020.05.014