Depressive Syndromes in Men With Hypogonadism in the TRAVERSE Trial: Response to Testosterone-Replacement Therapy.

CONTEXT: The effect of testosterone on depressive symptoms in men with hypogonadism remains incompletely understood. OBJECTIVE: We assessed the effects of testosterone-replacement therapy (TRT) in improving depressive symptoms in hypogonadal men with and without depressive symptoms enrolled in the TRAVERSE cardiovascular safety trial. METHODS: A randomized, placebo-controlled, double-blind study was conducted at 316 trial sites. Participants included men, aged 45 to 80 years, with 2 fasting testosterone levels less than 300 ng/dL, 1 or more hypogonadal symptoms, cardiovascular disease (CVD), or increased risk of CVD. We evaluated 3 subgroups of participants: (1) men with rigorously defined, late-life-onset, low-grade persistent depressive disorder (LG-PDD, previously "dysthymia"); (2) all men with significant depressive symptoms (Patient Health Questionnaire-9 Score >4); and (3) all randomly assigned men. Intervention included 1.62% transdermal testosterone or placebo gel. Outcome measures included the proportions of participants (1) meeting criteria for LG-PDD or (2) with significant depressive symptoms; and changes in depressive symptoms, energy, sleep quality, and cognition in testosterone-treated vs placebo-treated men in the 3 subgroups. RESULTS: Of 5204 randomly assigned participants, 2643 (50.8%) had significant depressive symptoms, but only 49 (1.5%) met rigorous criteria for LG-PDD. Among those with LG-PDD, there was no significant difference in any outcome measure between the TRT and placebo groups, possibly reflecting low statistical power. In men with significant depressive symptoms (n = 2643) and in all randomly assigned participants (n = 5204), TRT was associated with modest but significantly greater improvements in mood and energy but not cognition or sleep quality. CONCLUSION: Depressive symptoms are common in middle-aged and older men with hypogonadism but LG-PDD is uncommon. TRT is associated with small improvements in mood and energy in hypogonadal men with and without significant depressive symptoms.

Testosterone and mood in aging men.

Age-associated hypothalamic-pituitary-gonadal (HPG) axis hypofunction, or partial androgen deficiency of the aging male, is thought to be responsible for various age-associated conditions such as reduced muscle and bone mass, mobility limitations, frailty, obesity, sleep apnea, cognitive impairment, sexual dysfunction, and depression. It has been difficult to establish consistent correlations between these symptoms and plasma testosterone levels in middle-aged men, but testosterone replacement does lead to improved muscle strength, bone density, and sexual function. This article focuses on the relationship between testosterone and mood in older men, and the treatment of age-related depression with exogenous testosterone.

Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial.

Testosterone replacement is the most effective treatment for sexual dysfunction in hypogonadal men. Comorbid depression and antidepressant side effects may reduce its influence. The authors conducted a 6-week, double-blind, placebo-controlled clinical trial of testosterone gel versus placebo gel in men with major depressive disorder who were currently taking a serotonergic antidepressant and exhibited low or low-normal testosterone level. A total of 100 men were enrolled at 2 study sites (Boston, Massachusetts, USA, and Tel Aviv, Israel). The effects of testosterone augmentation on sexual functioning were determined using domain scores on the International Index of Erectile Function (IIEF). Complete pre- and posttrial IIEF data were available for 63 subjects. Men randomized to testosterone (n = 31) and placebo (n = 32) were similar in age, baseline testosterone levels, and baseline IIEF scores. At study termination, men randomized to placebo showed virtually no change from baseline in mean (95% CI) IIEF score (-0.7 [-6.5, 5.2]), whereas those receiving testosterone exhibited a substantial increase (15.8 [8.5, 23.1]). The estimated mean difference between groups was 16.8 [7.5, 26.1]; p = .001 by linear regression with adjustment for age and study site. There were also significant between-group differences in each of the 5 IIEF subscales, as well as on the single question involving ejaculatory ability (p ≤ .03 in all cases). Effect sizes in these comparisons remained little changed, and generally remained statistically significant, when we further adjusted for change in depression scores on the Montgomery Asberg Depression Rating Scale. It is notable that the subgroup of men with the highest baseline testosterone levels showed virtually the same improvement as those with lower levels, suggesting that the observed improvement was unlikely to be due simply to correction of hypogonadism alone. In depressed men with low or low-normal testosterone levels who continued to take serotonergic antidepressants, treatment with exogenous testosterone was associated with a significant improvement in sexual function, particularly including ejaculatory ability.

Parallel-group placebo-controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment.

Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant augmentation strategy for depressed men. We sought to assess the antidepressant effects of testosterone augmentation of a serotonergic antidepressant in depressed, hypogonadal men. For this study, we recruited 100 medically healthy adult men with major depressive disorder showing partial response or no response to an adequate serotonergic antidepressant trial during the current episode and a screening total testosterone level of 350 ng/dL or lower. We randomized these men to receive testosterone gel or placebo gel in addition to their existing antidepressant regimen. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS) score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression Scale, and the Quality of Life Scale. Our primary analysis, using a mixed effects linear regression model to compare rate of change of scores between groups on the outcome measures, failed to show a significant difference between groups (mean [95% confidence interval] 6-week change in HDRS for testosterone vs placebo, -0.4 [-2.6 to 1.8]). However, in one exploratory analysis of treatment responders, we found a possible trend in favor of testosterone on the HDRS. Our findings, combined with the conflicting data from earlier smaller studies, suggest that testosterone is not generally effective for depressed men. The possibility remains that testosterone might benefit a particular subgroup of depressed men, but if so, the characteristics of this subgroup would still need to be established.

Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial.

Mid-life onset male dysthymic disorder (DD) seems to be a distinct clinical condition with limited therapeutic options. Testosterone replacement is mood-enhancing and has been proposed as an antidepressant therapy, though this strategy has received limited systematic study. We therefore conducted a six-week double-blind placebo-controlled clinical trial in 23 men with DD and with low or low-normal testosterone (T) level (i.e, screening total serum testosterone <350 ng/dL). Enrolled men were randomized to receive intramuscular injections of 200 mg of testosterone cypionate or placebo every 10 days. The primary outcome measures were the Clinical Global Impression (CGI) improvement score and the 21-item Hamilton Depression Rating Scale (HDRS) score.Twenty-three patients were randomized. The mean (SD) age of the enrolled patients was 50.6 (7.0) years and that of total testosterone level was 339 (93) ng/dL. The median duration of the current dysthymic episode was 3.6 (2.3) years, and the mean (SD) HDRS was 14.0 (2.9). After the intervention, the mean HDRS score decreased significantly more in the testosterone group (7.46 [4.56]) than in the placebo group (1.8 [4.13], t21 = -3.07, P = 0.006). Remission, defined as a CGI improvement score of 1 or 2 and a final HDRS score lower than 8, was achieved by 7 (53.8%) of 13 in the testosterone group and 1 (10%) of 10 in the placebo group (P = 0.03). Testosterone replacement may be an effective antidepressant strategy for late-onset male dysthymia.

An open-label pilot study to evaluate the efficacy of sildenafil citrate in middle-aged men with late-onset dysthymia.

Late onset dysthymic disorder (DD) in middle-aged and elderly men responds poorly to established antidepressants. Previous studies noted an improvement in mood accompanying sildenafil citrate treatment for erectile dysfunction. We sought to evaluate whether sildenafil's mood effects were independent of the effect on erectile function. A 6-week open label study was conducted with 20 male participants, aged 41-60 who were diagnosed with DD and who had normal erectile function. Participants were treated with sildenafil citrate 25 mg per day for 6 weeks. The primary outcome measure was the 21-item Hamilton Depression Rating Scale. Depressive and sexual symptoms were also evaluated using self-report questionnaires. Treatment with sildenafil resulted in a significant reduction in Hamilton Depression Rating Scale mean scores: from 14.61 +/- 3.5 at baseline to 6.39 +/- 5.13 at end of study (F(3,51) = 32.52, p

Testosterone and depression in men.

PURPOSE OF REVIEW: The purpose of the review is to update the current literature regarding the role, if any, that testosterone plays in depressive illness. We have considered the influences on depression of endogenous testosterone, that is, hypogonadism and depression; and exogenous testosterone, that is, as a potential antidepressant. RECENT FINDINGS: Studies do not support a consistent relationship between testosterone level and mood. There may be vulnerable subpopulations in whom hypogonadism contributes to depression; and chronic depressive illness may lead to hypogonadism in some men. Results from multiple randomized, controlled clinical trials are conflicting. Most do not support testosterone as a broadly effective antidepressant, but it may be effective in carefully selected populations, such as hypogonadal men, antidepressant-resistant men, men with early onset depression, and/or HIV-infected men. SUMMARY: There is little support for a pervasive influence of testosterone on mood.

Testosterone supplementation for depressed men: current research and suggested treatment guidelines.

Several lines of accumulating evidence suggest that testosterone might be effective for the treatment of depression, especially in older men who exhibit low testosterone levels. However, despite the potential promise of this approach, the available literature of controlled studies of testosterone in depression remains extremely limited. Therefore, testosterone treatment of depression must still be considered an experimental procedure. At the present state of research, it appears that testosterone might most likely show benefit as an augmentation strategy in men who exhibit low or borderline testosterone levels and who show only a partial response to conventional antidepressants. In this article, we provide some suggested practical guidelines for the treatment of such individuals. However, it should be recognized that these suggestions are tentative and will likely require revision as additional data become available.

Androgens and the aging male.

In contrast to women, men do not experience a sudden cessation of gonadal function comparable to menopause. However, there is a progressive reduction in male hypothalamic-pituitary-gonadal (HPG) axis function: testosterone levels decline through both central (pituitary) and peripheral (testicular) mechanisms, and there is a loss of the circadian rhythm of testosterone secretion. The progressive decline in testosterone levels has been demonstrated in both cross-sectional and longitudinal studies, and overall at least 25% of men over age 70 meet laboratory criteria for hypogonadism (ie, testosterone deficiency). Such age-associated HPG hypofunctioning, which has been termed "andropause," is thought to be responsible for a variety of symptoms experienced by elderly men, including weakness, fatigue, reduced muscle and bone mass, impaired hematopoiesis, sexual dysfunction (including erectile dysfunction and loss of libido), and depression. Although, it has been difficult to establish correlations between these symptoms and plasma testosterone levels, there is some evidence that testosterone replacement leads to symptom relief, particularly with respect to muscle strength, bone mineral density, and erectile dysfunction. There is little evidence of a link between the HPG axis hypofunctioning and depressive illness, and exogenous androgens have not been consistently shown to have antidepressant activity. This article reviews the relationship between androgens, depression, and sexual function in aging men.

The sexual effects of testosterone replacement in depressed men: randomized, placebo-controlled clinical trial.

Symptoms of male hypogonadism such as low libido and erectile dysfunction (ED) respond to testosterone (T) replacement. In hypogonadal men with major depressive disorder (MDD), the extent to which T replacement alleviates sexual symptoms of hypogonadism is not known. We conducted 6 week double-blind placebo-controlled clinical trial in men with low and low-normal T levels (i.e., total T

Efficacy and safety of sildenafil in men with serotonergic antidepressant-associated erectile dysfunction: results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy of short-term treatment with sildenafil citrate in men with serotonin reuptake inhibitor (SRI)-associated erectile dysfunction (ED). METHOD: Men (aged>or=18 years) with major depressive disorder (MDD; DSM-IV criteria) in remission and taking SRIs who experienced SRI-associated ED were enrolled in this multicenter, 6-week, randomized, flexible-dose, double-blind, placebo-controlled trial. The primary study measures were questions 3 (Q3: frequency of penetration) and 4 (Q4: frequency of maintained erections after penetration) of the International Index of Erectile Function (IIEF) questionnaire. Secondary study measures were all other questions and domains of the IIEF, the Erectile Dysfunction Index of Treatment Satisfaction (EDITS), a global efficacy questionnaire (GEQ), and a patient-maintained event log of sexual activity. RESULTS: Patients receiving sildenafil (N=71) versus placebo (N=71) reported significantly higher mean+/-SE scores on Q3 (3.9+/-0.2 vs. 3.1+/-0.2, p=.003) and Q4 (3.7+/-0.2 vs. 2.8+/-0.2, p<.001) of the IIEF and significantly higher scores on all domains of the IIEF. Patients receiving sildenafil also reported significantly improved scores on all questions of the EDITS questionnaire (p<.02) and the GEQ (p<.0001) and an increased number of successful sexual intercourse attempts per week (p<.0001) compared with patients receiving placebo. All patients remained in MDD remission (score

Intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled clinical trial.

BACKGROUND: Treatment-resistant depression is a persistent clinical problem. Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant supplement, although this strategy has received limited systematic study. OBJECTIVE: The aim of the study was to examine the mood effects of testosterone supplementation to a serotonergic antidepressant in men with treatment-resistant depression. METHOD: Twenty-six healthy adult men with major depressive disorder, partial or nonresponse to 2 adequate antidepressant trials during the current episode, and currently using a selective serotonin reuptake inhibitor were randomized under double-blind conditions to receive intramuscular injections of escalating doses of testosterone or placebo, in addition to their existing selective serotonin reuptake inhibitor regimen, for 6 weeks. The main outcome measure was the Hamilton Rating Scale for Depression score. RESULTS: The mean age was 46.4 +/- 10.8 years; mean total testosterone level, 417.5 +/- 197 ng/dL; mean baseline Hamilton Rating Scale for Depression score, 22.2 +/- 5.2; and median duration of the current depressive episode, 6.3 +/- 10.6 years. Hamilton Rating Scale for Depression scores decreased significantly in both testosterone (8.4) and placebo (7.4) groups. Antidepressant response, defined as a 50% decline in Hamilton Rating Scale for Depression score, was achieved by 53.8% (7/13) in the testosterone group and 23.1% (3/13) in the placebo group (P = 0.226). CONCLUSION: Both injectable testosterone and placebo supplementation to selective serotonin reuptake inhibitor were associated with improvement in mood; group differences were not distinguishable in this small sample of predominantly eugonadal men with treatment-resistant depression.

An open trial of venlafaxine for the treatment of late-life atypical depression.

OBJECTIVES: The atypical subtype in patients with major depressive disorder is characterized by mood reactivity, significant weight gain or increase in appetite, hypersomnia, leaden paralysis and a long-standing pattern of interpersonal rejection sensitivity. Though atypical depression is well documented in younger patients, little attention has been paid to the atypical subtype in samples of late-life depressed patients. This study reports the patient characteristics and treatment results of an eight-week open-label trial of venlafaxine in a sample of older depressed patients with atypical subtype. METHODS: Patients received fixed dosing schedule (up to 300 mg/day) of venlafaxine (Effexor XR) for 8 weeks. RESULTS: In this sample of 17 patients, the mean age was 65.6 years and 77% were female. Most strikingly, 53% of patients presented with late-onset atypical depression defined as first episode after the age of 50. Fifteen of the 17 patients (88%) completed the eight-week treatment trial. The mean score on the HRSD 24-item decreased from 22.2 +/- 5.1 at baseline to 11.8 +/- 8.9 (p<0.001), and the mean total atypical item score decreased from 6.2 +/- 1.6 to 2.8 +/- 2.0 (p < 0.001). Remission was defined as a final HRSD < or = 10 and a 50% reduction in baseline HRSD score. The intent-to-treat remission rate was 65% and the completer remission rate was 73%. CONCLUSIONS: In this sample of late-life patients with atypical depression venlafaxine treatment was reasonably effective and well tolerated. However, the effectiveness of venlafaxine in this study must be considered in the context that this was an open trial of antidepressant medication. Insufficient attention has been given to the atypical subtype in late-life depression. Whether late-onset atypical depression is significantly different from early-onset atypical depression, and whether late-onset patients with atypical depression are significantly different from late-onset patients with other depressive subtypes are questions of compelling interest.

The aging male: androgens, erectile dysfunction, and depression.

In contrast to women, men do not experience a sudden cessation of gonadal function comparable to menopause. However, there is a progressive reduction in hypothalamic-pituitary-gonadal (HPG) axis activity in aging men: testosterone levels decline and there is a loss of the circadian rhythm of testosterone secretion. Such progressive HPG-axis hypofunctioning is thought to be responsible for some signs and symptoms that are common in elderly men such as fatigue, reduced muscle and bone mass, sexual dysfunction, and depression. Yet, such presumed hypogonadal sequelae have not been correlated with testosterone levels. Unlike the profound effects of replacement therapy in young men with frank hypogonadism, testosterone replacement in men with age-related mild hypogonadism is not apparently effective in reversing these symptoms. This article reviews the relationship between androgens, sexual function, and depression in aging men.

High-dose sildenafil citrate for selective serotonin reuptake inhibitor-associated ejaculatory delay: open clinical trial.

BACKGROUND: Selective serotonin reuptake inhibitor (SSRI)-induced ejaculatory delay is a common problem that has no treatment with established efficacy. Sildenafil citrate is effective for erectile dysfunction and appears to be safe at doses up to 200 mg. METHOD: We enrolled men who were in remission from depression according to DSM-IV criteria and who reported that they had developed new-onset ejaculatory delay in the setting of SSRI treatment. Enrolled patients were instructed to use 25 mg of sildenafil 1 hour prior to sexual activity on at least 2 occasions. If this was not effective for the ejaculatory delay, they were instructed to increase the dose progressively up to a maximum of 200 mg. We compared baseline sexual functioning to 2 phases of open treatment: low-dose phase (sildenafil 25-100 mg) and high-dose phase (sildenafil 150-200 mg). The primary outcome measure was a modified, self-report Clinical Global Impressions (CGI) scale that was specific for erectile (CGI-EF) and ejaculatory (CGI-EJF) aspects of sexual function. RESULTS: Twenty-one men (mean age = 56 years) with major depressive disorder (MDD) in remission and SSRI-associated ejaculatory delay enrolled in the study and received sildenafil. At baseline, 14 of 21(67%) had comorbid erectile dysfunction. At the low-dose phase follow-up assessment, 12 of 14 achieved full erectile dysfunction remission, and 4 of 21 achieved ejaculatory delay remission. Sixteen patients with persistent ejaculatory delay were eligible for the high-dose phase: 5 withdrew from the study, 4 increased to a maximum dose of 150 mg, and 6 increased to a maximum dose of 200 mg. The 1 patient who had clinically significant erectile dysfunction and ejaculatory delay reported improvement of both conditions after the high-dose phase. Of the 10 patients who had ejaculatory delay without significant erectile dysfunction and who chose to take high-dose sildenafil, 9 reported a significant clinical improvement in ejaculatory delay (CGI-EJF improvement score of 1 or 2) and 7 achieved full remission (CGI-EJF severity score of 1 or 2 and CGI-EJF improvement score of 1 or 2). CONCLUSION: In this open clinical trial with men who had SSRI-induced ejaculatory delay, high-dose sildenafil appeared to be effective in reducing ejaculatory latency.

Testosterone deficiency and mood in aging men: pathogenic and therapeutic interactions.

In contrast to women, men do not experience a sudden cessation of gonadal function comparable to menopause. However, there is a progressive reduction in hypothalamic-pituitary-gonadal (HPG) function in aging men: testosterone (T) levels decline through both central (pituitary) and peripheral (testicular) mechanisms and there is a loss of the circadian rhythm of T secretion. In cohorts of men 75 years of age, mean plasma T levels are 35% lower than comparable young men, and more than 25% of men over 75 appear to be T-deficient. Such age-associated T deficiency, which has been termed 'andropause', is thought to be responsible for a variety of symptoms experienced by elderly men, such as weakness, fatigue, reduced muscle and bone mass, impaired haematopoiesis, oligospermia, sexual dysfunction, depression, anxiety, irritability, insomnia and memory impairment. However, it has been difficult to establish correlations between these symptoms and plasma T levels. Nevertheless, there is some evidence that T replacement leads to symptom relief, particularly with respect to muscle strength, bone mineral density, and haematopoiesis. Studies to date on the specific association between psychiatric symptoms, such as depressed mood, and T levels have been methodologically flawed. Overall, data suggest that although hypogonadism is not central to major depressive disorder (MDD), HPG hypofunction may have aetiological importance in mild depressive conditions, such as dysthymia.

Depression, antidepressant therapies, and erectile dysfunction: clinical trials of sildenafil citrate (Viagra) in treated and untreated patients with depression.

Erectile dysfunction (ED) and depression are highly prevalent conditions and frequently occur concomitantly in predisposed individuals. Men with ED and depression are also likely to have other comorbid conditions, including diabetes, hypertension, and heart disease. Because ED is also a common adverse effect of some medications for these conditions, patients are frequently noncompliant with treatment. Sildenafil citrate (Viagra) is effective in treating ED of a broad range of etiologies, suggesting that it may be equally beneficial in patients with ED that is associated with depressive symptoms and in those with ED resulting from serotonergic reuptake inhibitor (SRI) antidepressant treatment. We review the results of 3 randomized, placebo-controlled trials and a retrospective analysis of data pooled from 10 clinical trials that examine the efficacy of sildenafil in treating ED associated with depression and as an adverse effect of SRI treatment. The results suggest that sildenafil is efficacious as a first-line treatment for ED in men with untreated minor depression, in men with ED that is refractory to successful SRI treatment of depression, and in those whose depression was successfully treated but who developed ED as a consequence of SRI treatment. Given the complex interrelations among ED, depression, and other comorbid conditions, the key to proper management is a comprehensive evaluation, including sexual function, and an accurate differential diagnosis.