Gonadotropin-releasing hormone (GnRH) analogues and risk of depression

Some data suggest that the use of GnRH analogs is associated with an increased risk of depression, which can be severe. The data sheets and package inserts for these drugs in Europe will be updated.

Following the report of a study in Japan describing cases of depression, including suicide, in women with endometriosis treated with GnRH1 analogues, the marketing authorisation holder of leuprorelin carried out an epidemiological study with the GPRD (General Practitioner Research Database). This study showed an increased risk of new cases of depression in endometriosis and prostate cancer patients and an increased risk of suicidal behavior in prostate cancer patients treated with GnRH analogues.

For this reason, the national drug agencies of the European Union decided to evaluate in detail the new available evidence in this respect, taking into account the risk of this type of alterations in patients with prostate cancer or other alterations which constitute the indications of GnRH analogues. On the other hand, it is known that prostate cancer patients treated with GnRH analogues have a higher risk of developing depression or of worsening a pre-existing depression. In addition, there is also a potential risk of behavioral changes and depression in women treated with GnRH analogs for non-neoplastic hormone-dependent conditions.

The active ingredients included in this review have been: buserelin, goserelin, histrelin, leuprorelin, nafarelin and triptorelin.

The data evaluated in this review are from the study conducted with the GPRD database and from a previous safety assessment of leuprorelin based on published data2-11, as well as from spontaneous reporting of suspected adverse reactions.

The results of the study conducted with the GPRD database showed a rate of new cases of depression of 1 to 10 cases per 100 patient-years in men and women treated with GnRH analogues.

In patients with endometriosis treated with GnRH analogues there was an increase in risk of approximately 50% (RR 1.46, 95% CI 1.12-1.89), although the risk observed overlaps with that obtained in unexposed patients (RR 1.38, 95% CI 1.29-1.48).

In this same study, for patients with prostate cancer, a RR of new cases of depression of 1.97 (95% CI 1.86-2.10) was obtained, which was higher than the increased risk associated with prostate cancer itself (RR 1.45; 95% CI 1.35-1.55). An increased risk of suicidal behavior was observed in these patients treated with GnRH analogues, although the small number of cases and the retrospective and observational character of this study, make these results should be interpreted with caution.

The review of published articles2-12 and cases from spontaneous reporting show that depression and behavioral changes are known risks related to the reduction of estrogen/testosterone levels during treatment with GnRH analogues.

The conclusion of this review has been that the risk of depression and behavioural changes should be consistently included in the data sheets of these drugs. The data sheets and package inserts will be updated to include warnings about the risk of depression, which can be serious, as well as the need to inform the patient and establish timely treatment if necessary. Changes in behaviour and depression shall be included in the section on adverse reactions.

References:

• Japan Endometriosis Association publishes third national study. April 2007; available under: http://endometriosis.org/news/support-awareness/japan-endometriosis-association-announces-significantly-adverse-effects-of-gnrh-use/
• Cherrier MM, Aubin S, Higano CS. Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psychooncology. 2009; 18: 237-247.
• Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of the “androgen deprivation syndrome” in men receiving androgen deprivation for prostate cancer. Arch Intern Med. 2006; 166: 465-471.
• Schmidt PJ, Berlin KL, Danaceau MA, Neeren A, Haq NA, Roca CA, Rubinow DR. The effects of pharmacologically induced hypogonadism on mood in healthy men. Arch Gen Psychiatry. 2004; 61: 997-1004.
• Rosenblatt DE, Mellow A. Depression during hormonal treatment of prostate cancer. J Am Board Fam Pract. 1995; 8: 317-320.
• Sepulcri Rde P, do Amaral VF. Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol. 2009; 142: 53-56.
• Steingold KA, Cedars M, Lu JK, Randle D, Judd HL, Meldrum DR. Treatment of endometriosis with a long-acting gonadotropin-releasing hormone agonist. Obstet Gynecol. 1987; 69: 403-411.
• Warnock JK, Bundren JC. Anxiety and mood disorders associated with gonadotropin-releasing hormone agonist therapy. Psychopharmacol Bull. 1997; 33: 311-316.
• Bloch M, Azem F, Aharonov I, Ben Avi I, Yagil Y, Schreiber S, Amit A, Weizman A. GnRH-agonist induced depressive and anxiety symptoms during in vitro fertilization-embryo transfer cycles. Fertil Steril. 2011; 95: 307-309.
• Friedman AJ, Hoffman DI, Comite F, Browneller RW, Miller JD. Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group. Obstet Gynecol. 1991; 77: 720-725.
• Toren P, Dor J, Mester R, Mozes T, Blumensohn R, Rehavi M, Weizman A. Depression in women treated with a gonadotropin-releasing hormone agonist. Biol Psychiatry. 1996; 39: 378-82.

NOTE THAT IN JAPAN THEY HAVE KNOWN THIS DATA SINCE 2007 AND THAT IT ARRIVES IN SPAIN IN 2014.

THE LUCK OF JAPANESE WOMEN, THEIR COUNTRY LOOK FOR IT, IN SPAIN NOT.

Endometriosis Association of Japan publishes third national study
04 2007
The Japanese Endometriosis Association has announced preliminary results from the National Endometriosis Survey that show negative emotional effects of GnRH analogs when used in endometriosis

The Japanese Endometriosis Association (JEMA), founded in 1994, conducts a national survey of endometriosis every five years.

Their 2006 data (n = 668) shows that 28% of respondents suffer from depression while using GnRH-a, with 16% having suicidal thoughts, and 2% actually attempting suicide.

JEMA has often had meetings with and made requests to the Ministry of Health, Labour and Welfare (MHLW) in recent years, and has strengthened its political links. It has repeatedly called for increased use of standard global medical treatment in Japan, including the low-dose contraceptive pill, promotion of laparoscopic surgery for diagnosis, and a reduction in the empirical use of GnRH-because of previously reported side effects.

The low-dose contraceptive pill was not approved until September 1999 in Japan. However, its use has not been widespread because MDs are hesitant to prescribe pills without insurance coverage, and with a lack of knowledge and experience they would not recommend to patients. And so, since the fall of 2002, JEMA has been involved in the project for which it is applying for health insurance coverage for endometriosis.

More recently JEMA has translated the ESHRE Directive for the diagnosis and treatment of endometriosis into Japanese. The guideline is reviewed annually, by an international panel of experts, according to evidence-based principles.

JEMA has been educating women with endometriosis and working with health professionals in Japan for the last 13 years. It publishes a bi-annual and semi-monthly electronic newsletter.

Masumi Inui, JEMA’s Executive Representative, is an author of books on endometriosis and writer/editor of JEMA publications, and she is an occasional guest speaker at medical meetings or television programs as a recognized endometriosis specialist.