CLS 306 Men and Women s Health Research Paper Is testosterone therapy a safe and effective approach to treating major depression in adult males? Introduction: Major depressive disorder (MDD) is a debilitating mental illness with extensive implications on the physical, mental, and emotional health of sufferers. The prevalence of MDD in the general population has been estimated between 2.3-4.9%, with a lifetime occurrence of about 13.3-17.1%; depressive conditions as a whole have an approximate economic burden of $86 billion annually in the U.S. alone 1. While the use of antidepressant medication has been helpful in treating these mental illnesses, their overall safety and effectiveness is often questioned. Some epidemiological studies have found an association between depressive symptoms in the aging male and reduced testosterone status; however, this relationship is complicated by other factors such as medical illness, obesity, smoking and alcohol use, and diet and lifestyle 2. Early trials attempting to reverse or limit depressive symptoms through the use of testosterone supplementation have yielded mixed results. Therefore, the purpose of this discussion is to outline the fundamental objective(s) of testosterone supplementation in adult males, and to ultimately develop a clinical recommendation as to whether supplementation is, at this moment, a safe, effective, and appropriate tool in the management of male depressive disorder. Male Depressive Disorders: The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM- IV), defines MDD as either depressed mood or reduced interest in and pleasure from activities (or both), lasting for at least two weeks, and accompanied by at least four other secondary symptoms, including: excessive guilt or feelings or worthlessness; reduced energy or fatigue; diminished ability to concentrate or make decisions; loss or increase of either appetite or weight; psychomotor agitation; or thoughts of suicide, death, or suicidal behavior 1. Major depression is a leading cause of disability worldwide; it has been shown to increase suicidality, worsen many medical conditions, and lead to decreased social and workplace performance 3. In males specifically, signs and symptoms of depression may include, but are not limited to: feeling hopeless, irritable, anxious, or angry; decreased libido; thoughts of suicide; a perceived inability to meet responsibilities of work or family; and physical symptoms such as aches or pains, headaches, or digestive problems 4. While Page 1 of 7
the impact of mental illness can be extensive across all populations, it is important to investigate the aging male specifically in the context of depressive symptoms and the age- related decline of testosterone levels. Testosterone Levels and the Aging Male: It is generally well- accepted that an age- related decline in male testosterone levels exists, although there is large inter- individual variation 5. More specifically, the aging process, which reduces sensitivity of the hypothalamic- pituitary- gonadal (HPG) axis, as well as Leydig cell function, actually results in a lowering of both total and free testosterone levels, the latter of which have been shown to decline at a rate of 1% per year after 40 years of age 2. In fact, approximately 30% of men aged 60-70 years, and 70% of men aged 70-80 years, are thought to have low testosterone levels (below about 350 ng/dl) 6. Physiologically, testosterone is necessary for many crucial functions, including spermatogenesis, penile function, secondary sex characteristics, lean muscle mass, bone density, and normal sexual behavior and cognitive function 6. Low testosterone status has been associated with many physical and psychological detriments, including sexual dysfunction (oligospermia, decreased libido, impotence), fatigue, reduced muscle mass, increased risk of osteoporosis, anxiety, irritability, insomnia, reduced cognitive function, and ultimately an increased risk of depressive symptoms 2, 7. Interestingly, testosterone has also been linked with certain personality traits for example, males with low levels of testosterone are typically found to be friendly, docile, and intellectual, while males with high levels have been shown to be more aggressive, impulsive, and unfriendly 8. Unfortunately, studies have not consistently shown a direct correlation between testosterone levels and MDD. This is possibly due to the complex relationship between psychological health and testosterone status, in that there is often overlap in terms of depressive symptoms such as low libido, fatigue, loss of confidence, and irritability 5. In a recent study, 3413 men (average age 60 years) completed the Hopkins Symptom Checklist- 10 (SCL- 10) psychological questionnaire and were analyzed for total and free testosterone levels. Men in the lowest tenth percentile for testosterone levels did have significantly higher SCL- 10 scores, and higher anxiety symptoms, compared to men in the highest percentile; however, men with more pronounced symptoms of MDD did not necessarily have lower testosterone levels 5. The authors noted that the questionnaire, while valid, may not have been extensive enough to elicit a more significant Page 2 of 7
relationship, and that testosterone samples should have been taken more consistently (in the morning due to diurnal variation), as opposed to at random 5. Other authors have found similar relationships; therefore, lower testosterone levels may increase the risk of depression in older males, however the association appears to be highly variable. Another reason for the variability between testosterone status and depressive symptoms in the aging male appears to result from androgen receptor genetics and polymorphisms. Very recently, a cross- sectional study of 296 men over the age of 50 years examined the relationship between testosterone status and androgen receptor cytosine- adenosine- guanine (AR- CAG) repeat polymorphisms 9. The authors linked this to depressive symptoms by including subjects from a depression clinic, an andrology clinic, and a community sample. The two clinical samples had significantly different AR- CAG repeats and higher depression levels than the community sample, however the polymorphisms were not associated with testosterone levels. The authors do note that, because depressed subjects have been known to decline participation in clinical trials, the prevalence of depression in the community setting may have been underrepresented. Further, only self- administered questionnaires were used to assess depressive symptoms, whereas a clinical interview and the development of a DSM- IV diagnosis may have been more accurate 9. Therefore, while genetic differences may not be significant enough to result in a causative relationship with testosterone status, they may certainly suggest a vulnerability to depressive symptoms. Conventional Treatment for Depression: Major depression is a relatively common disorder that can be significantly improved by antidepressant medication, the use of which has doubled in the U.S. between 1995 and 2002 10. About 50% of all patients prescribed an antidepressant do respond to therapy, however some residual symptoms remain, as only about one third of patients achieve complete resolution of symptoms 10. Unfortunately, almost all antidepressant medications have some associated side effects, and do not necessarily reduce the risk of suicide, which has been shown to be almost twenty times higher than normal in patients with MDD 10. The most common antidepressant medications prescribed are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin- norepinephrine reuptake inhibitors (SNRIs). Some systematic reviews have found small differences between treatment and placebo in terms of effectiveness, and have noted significant safety concerns. TCAs generally have a higher risk for adverse cardiovascular events, while side Page 3 of 7
effects for SSRIs/SNRIs include agitation, insomnia, gastrointestinal complaints, and sexual dysfunction drug/herb interactions are common with all three agents 10. While concerns continue to mount regarding the safety and efficacy of conventional antidepressant medication, and the evidence expands for the relationship between testosterone status and depressive symptoms in the aging male, many researchers have began to focus on a possible role of testosterone supplementation in the management of depression. Evidence for Testosterone Supplementation: While the relationship between depressive disorders and testosterone status in the aging male still remains unclear, there has been some evidence to suggest that testosterone supplementation may be effective in this population. At the very least, it is thought that testosterone may be considered in cases where the patient has been partially- or un- responsive to conventional antidepressant treatment 11. In the past, the use of testosterone supplementation was challenging due to limitations in the route of administration. Oral testosterone (such as methyltestosterone) carries with it an increased risk of hepatotoxicity, while longer- lasting esters (such as enanthate and decanoate) have the benefit of intramuscular injection systems, but have been shown to be variable in level of testosterone they produce 11. The introduction of transdermal testosterone- delivery systems (such as gels and patches) have high compliance, low incidence of adverse events, and have been shown to reverse symptoms of hypogonadism, such as fatigue, depressed mood, and decreased sexual function 6. An early trial by Pope et al. (2003) assessed the ability of a 1% testosterone gel (10 g/d), or placebo, to improve depressive symptom scores over 8 weeks when given to 22 men (aged 30-65 years) with a diagnosis of refractory depression and a morning serum total testosterone of less than 350 ng/dl. Subjects receiving the testosterone gel had significantly improved scores on the Hamilton Depression Rating Scale (HDRS) and on the Clinical Global Impression Scale (CGIS), but not on the Beck Depression Inventory (BDI) 12. The authors did note several limitations of the study: the low number of subjects, the relatively short duration (8 weeks), the minimal eligibility screening (only 1 serum testosterone measurement, which may have unnecessarily excluded some subjects), and the fact that all subjects were allowed to continue taking their antidepressant medication 12. Therefore, while beneficial effects on depression scores were evident, it may be Page 4 of 7
possible that testosterone has a more adjunctive, as opposed to primary, role in the management of depression in these individuals. More recently, the same authors assessed the effectiveness of testosterone as an adjunct to treatment with a serotonergic antidepressant 13. The subjects were 100 depressed males aged 65 years or younger, with a testosterone level of less than 350 ng/dl, and who have had either partial or no response to antidepressant treatment. They were randomized to testosterone gel or placebo for 6- weeks, after which there were no significant differences between treatment and placebo groups for HDRS scores 13. Again, subjects were allowed to continue taking their conventional antidepressant medication, so it is difficult to gauge the true effectiveness of testosterone as a single primary therapeutic agent. Also, as discussed earlier, the age- related decline in testosterone status is most pronounced after 70-80 years of age, and therefore the subjects in this study may have been too young to elicit a true benefit of the supplementation. Finally, it is important to highlight a recent trial in patients with metabolic syndrome, a condition which has been associated with decreased testosterone status, sexual dysfunction, and depressive symptoms 7. Subjects (184 men with an average age of 52.1 years) were injected with 1000 mg (IM) testosterone undecanoate, or placebo, at 0, 6, and 18 weeks, and assessed for depressive symptoms using three scales at 0 and 18 weeks 7. Interestingly, all three scales had improved scores in men treated with testosterone, with the most benefit occurring in men with the lowest baseline total testosterone levels 7. While this study may not be applied to men without metabolic syndrome, it certainly helps illustrate the truly complex relationship between overall health, testosterone status, psychological well- being. Clinical Interpretation, Recommendations, and Conclusions: Currently, due to inconsistency among trials, and a limited number of trials examining the safety and efficacy of testosterone as a monotherapeutic agent, there is insufficient evidence to warrant the recommendation for the use of testosterone in treating major depressive disorder in males. Patients presenting with low or reduced testosterone status should always be examined for other causes of hypogonadism, including hypothalamic or pituitary disease, or neurological disorders 11. Testosterone supplementation is not without potential adverse effects as well, including gynecomastia, edema, or exacerbations of more serious illnesses like prostate cancer 2, 11. Page 5 of 7
Overall, some clinical recommendations can certainly be made based on promising research to date, and the accumulating evidence that suggests a strong relationship between the decreased testosterone status of the aging male and an increase in depressive disorders or symptoms. For example, several key trials discussed above have noted the beneficial effect of testosterone as an adjunctive therapy to conventional antidepressant medication. Therefore, testosterone may be especially indicated in patients who have been partially- or un- responsive to antidepressant treatment 2. Future studies should explore this relationship, as there may be potential to reduce the reliance on antidepressant medication, and therefore limit the incidence of adverse events. Clearly, and considering current projections that the elderly population will nearly double by the year 2050, the relationship between age- related testosterone decline and major depressive disorders in males requires immediate attention, as both of these conditions can have debilitating implications on both the health care system and the male patient. References: 1. Fava M, Cassano P. Mood Disorders: Major Depressive Disorder and Dysthymic Disorder. Comprehensive Clinical Psychiatry. Chapter 29, pp. 391-398. Massachusetts General Hospital. 2. Carnahan RM, Perry PJ. Depression in Aging Men: The Role of Testosterone. Drugs Aging. 2004; 21(6):361-376. 3. Gelenberg AJ, Hopkins HS. Assessing and Treating Depression in Primary Care Medicine. The American Journal of Medicine. 2007; 120:105-108. 4. Men and Depression. National Institute of Mental Health (U.S. Department of Health and Human Services, National Institutes of Health). NIH Publication No. QF 11-5300. 5. Berglund LH, Prytz HS, Perski A, Svartberg J. Testosterone levels and psychological health status in men from a general population: the Tromso study. The Aging Male. 2011; 14(1):37-41. 6. Lunenfeld B, Oettel M. Therapeutic potential of testosterone gels. Aging Health. 2009; 5(2);227-245. 7. Giltay EJ, Tishova YA, Mskhalaya GJ, Gooren LJ, Saad F, Kalinchenko SY. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. Journal of Sexual Medicine. 2010; 7:2572-2582. 8. Seidman SN, Walsh BT. Testosterone and depression in aging men. The American Journal of Geriatric Psychiatry. 1999; 7(1):18-34. 9. Schneider G, Nienhaus K, Gromoll J, Heuft G, Nieschlag E, Zitzmann M. Depressive symptoms in men aged 50 years and older and their relationship to genetic androgen receptor polymorphism and sex hormone levels in three different samples. The American Journal of Geriatric Psychiatry. 2011; 19(3):274-284. 10. Adams SM, Miller KE, Zylstra RG. Pharmacologic Management of Adult Depression. Am Fam Physician. 2008; 77(6):785-792, 795-796. 11. Kanayama G, Amiaz R, Seidman S, Pope HG. Testosterone supplementation for depressed men: current research and suggested treatment guidelines. Experimental and Clinical Psychopharmacology. 2007; 15(6):529-538. Page 6 of 7
12. Pope HG, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo- controlled trial. The American Journal of Psychiatry. 2003; 160(1):105-111. 13. Pope HG, Amiaz R, Brennan BP, Orr G, Weiser M, Kelly JF, Kanayama G, Siegel A, Hudson JI, Seidman SN. Parallel- group placebo- controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment. J Clin Psychopharmacol. 2010; 30:126-134. Page 7 of 7