Depression Yet Another Side Effect of ADT?

Fran Lowry

April 18, 2016

Androgen deprivation therapy (ADT) may be linked to depression in older men with localized prostate cancer, according to a retrospective review of nearly 80,000 patients older than 65 years.

Compared with men who did not receive ADT, men who received the hormonal therapy had significantly more depression requiring inpatient and outpatient psychiatric treatment. Also, among the ADT recipients, the risk for depression increased with longer duration of therapy.

The findings from the study were published online April 11 in the Journal of Clinical Oncology.

Depression is the latest adverse effect associated with ADT to come to the attention of researchers. It joins Alzheimer's disease, as reported by Medscape Medical News, and cognitive impairment, also reported by Medscape Medical News.

"Whenever doctors are recommending hormone therapy for patients, they need to have detailed discussions with them about the pros and cons, because the benefit of ADT is going to be different for every patient," senior author Paul L. Nguyen, MD, from Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

After noticing that some of his patients appeared to be "a bit more down" after being on ADT, Dr Nguyen decided to study a possible association.

He and his team analyzed data from the SEER-Medicare-linked database from 1992 to 2006. They identified 78,552 men older than 65 years with stage I to III prostate cancer who had not been diagnosed as having a psychiatric disorder within the prior year.

Dr Paul Nguyen

Of these patients, 33,882 (43.1%) received ADT within 6 months of their prostate cancer diagnosis. In the 2 years after diagnosis, 45.3% of the patients received ADT for a period of 6 months or less, 22.1% received ADT for 7 to 11 months, and 32.6% received ADT for 12 months or longer. Among the men who received ADT for 12 months or longer, 40.8% (n = 4515 patients) received it for 18 months or longer.

The 3-year cumulative incidence of new depression was 7.1% among the men who received ADT, compared with 5.2% among the men who did not (P < .001). They also had a higher incidence of inpatient (2.8% vs 1.9%, P < .001) and outpatient (3.4% vs 2.5%, P < .001) psychiatric treatment.

Compared with patients who did not undergo ADT, patients who received ADT had a 23% increased risk for new depression (adjusted hazard ratio [AHR], 1.23; 95% confidence interval [CI], 1.15 - 1.31, a 29% increased risk for inpatient psychiatric treatment (AHR, 1.29; 95% CI, 1.17 - 1.41), and a nonsignificant 7% increased risk for outpatient psychiatric treatment.

The longer patients were receiving ADT, the greater their risk for depression.

Duration Increased Risk P for Trend
≤ 6 months 12 % <.001
7 - 11 months 26 % <.001
≥12 months 37% <.001


A similar duration effect was seen for inpatient and outpatient psychiatric treatment (P for trend for both, <.001).

"Hormones control neurotransmitters in the brain. For example, we have mouse studies that show that there is a certain neurotransmitter that depends on male hormonal levels, and I think that there is a real chance that this is what is driving a lot of this new depression," Dr Nguyen said.

"The other side is, hormone therapy in men comes with a lot of side effects that can cause depression, such as less interest in sex, weight gain, loss of muscle mass, and fatigue," he said.

The main limitation of this study is that it is observational and retrospective, Dr Nguyen said.

Such limitations notwithstanding, "I do feel that depression is a real effect of ADT. I have seen it in my practice. Doctors should have a discussion with their patients and tell them that this is a possible side effect, and also discuss whether they need to be on androgen deprivation therapy in the first place," he said.

"If I were a patient and the doctor recommended androgen deprivation therapy, I would ask the doctor exactly how big is the prostate cancer benefit of this hormonal therapy for me, not for men in general, but for me personally," Dr Nguyen said.

Stacy Loeb, MD, from New York University, in New York City, agrees that doctors should discuss the issue with their patients.

Dr Stacy Loeb

"Doctors should tell their patients that a large US study of men with clinically localized prostate cancer showed an association between hormonal therapy and an increased risk of depression. This should be considered as part of the risk-to-benefit discussion for patients who are considering treatment options, including androgen deprivation therapy," Dr Loeb told Medscape Medical News.

But she cautioned that the results from the study do not mean that ADT should not be used.

"These results do not mean that androgen deprivation therapy should be avoided. In fact, there are some clinical scenarios where androgen deprivation therapy has been shown to improve oncologic outcomes, such as in combination with radiation therapy for high-risk localized prostate cancer. However, there are other clinical scenarios where hormonal therapy is optional, and the risks therefore must be weighed against the benefits," she said.

"We must also help our patients on hormonal therapy to manage the potential side effects. For example, exercise programs are very helpful to improve energy and might help reduce depression during hormonal therapy," Dr Loeb said.

Sumanta Pal, MD, from City of Hope Comprehensive Cancer Center, Duarte, California, told Medscape Medical News that the newly found association between depression and ADT adds to the list of effects typically linked with the therapy.

"Recently it has come to our attention that androgen deprivation therapy may be linked to Alzheimer's disease, and in the context of localized prostate cancer, this helps inform the discussion between radiation therapy and surgery, which is an ever-ongoing debate. The caveat is that usually, with radiation therapy, we use some duration of androgen deprivation," Dr Pal said.

The fact that utilization of resources for depression increased with duration of ADT "speaks to the fact that depression is associated with something other than just having the cancer. But what is challenging to tease out is whether there is some sort of a direct effect from the androgen deprivation therapy on, for instance, signaling in the brain leading to depression, or if there is an impact of some of the side effects of ADT, such as decreased libido, decreased sexual performance, and weight gain, which could be associated with depression as well," he said.

Dr Nguyen has financial relationships with Medivation, GenomeDx, and Ferring. Dr Loeb and Dr Pal report no relevant financial relationships.

J Clin Oncol. Published online April 11, 2016. Abstract


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