Erectile dysfunction (ED) is commonly associated with depressed mood and diminished quality of life (QoL), but few studies have investigated the causal associations involved. Therefore, we evaluated the correlation between several measures of mood, QoL, and sexual function in a retrospective analysis of a sample of depressed men (n=152), with ED enrolled in a clinical trial of sildenafil citrate (VIAGRA®). Strong correlations were observed at baseline among measures of erectile function (EF), mood, and overall QoL. Significant treatment effects were observed on all three domains, with significant interactions between changes in mood and QoL. Based on multiple regression and path analysis, a model was developed in which EF changes were associated with improved mood and quality of sexual life, which resulted in improved partner satisfaction, family life, and overall life satisfaction. These data suggest that QoL changes associated with ED therapy may be mediated by changes in sexual function, mood, and family relationships.
In the United States, 10 to 20 million men are estimated to have some degree of erectile dysfunction (ED), and it is well established that ED is associated with a wide range of psychosocial problems, such as decreased quality of life (QoL) and self-esteem and an increased incidence of depression and interpersonal relationshipproblems.1, 2, 3, 4 Numerous clinical and epidemiological studies have demonstrated that ED has a strong negative impact on QoL; for example, Jønler et al5 have shown that patients with loss of erectile function (EF) within the past year had significantly lower QoL than men without ED. Similarly, in other studies, men with a complaint of ED had poorer QoL than age-matched men from the general population.6, 7 Some data also suggest that ED worsens psychological adaptation to comorbid medical conditions; in a study of 1460 diabetic men, those with comorbid ED had lower QoL, significantly higher levels of diabetes-specific health distress, worse psychological adaptation to and acceptance of diabetes, and a less satisfactory sexual life.8 Moreover, these men were more easily frustrated and discouraged by their diabetes, which could lead to worse metabolic control.
General health and QoL can be negatively affected by the breakdown of a significant personal relationship, which is one of the most stressful life events. A UK-based survey demonstrated that men with ED and multiple risk factors had poorer QoL than men with ED and no risk factors; in addition, up to 28% of these men believed that their sexual dysfunction was directly responsible for the termination of their last relationship.7 One limitation of these two studies7, 8 is the fact that, although a correlation between QoL and ED was demonstrated, the effects of ED treatment on QoL were not examined.
Indeed, whereas most studies have demonstrated a clear relation between ED and QoL, the strength of association has varied significantly from one study to another, partially because of the broad range of QoL measures used. QoL has not been measured in a consistent way, studies have not controlled for potential confounding effects of mood or partner relationships, and the nature of the causal relation has not been systematically examined in any of these studies. This is the first study to investigate the specific mechanisms by which ED treatment leads to improved QoL.
Epidemiological studies have demonstrated a highly significant association between ED and depression, irrespective of age, marital status, or comorbidities.2, 3, 9, 10, 11 For example, in the Massachusetts Male Aging Study,9 patients with depression had a 1.8-times higher chance of concomitant ED than patients without depression, whereas in another study evaluating men with ED or benign prostatic hyperplasia, men with ED were 2.6 times more likely to report depressive symptoms.2 Similarly, a history of depression was significantly associated with the prevalence of ED in a Brazilian study of sexual behavior.11
However, the coexistence between ED and depression is complex, and the causal relation remains unclear. The psychosocial distress that often accompanies ED may cause depressive illness in susceptible individuals, or ED can be one of the symptoms of a major depressive disorder, which is associated with decreased libido, diminished EF, and decreased sexual activity.12 In addition, the use of antidepressants has been linked to problems with ejaculation, orgasm, desire, and erections.13, 14, 15 Furthermore, a subgroup of men with major depressive disorder developed a reversible loss of nocturnal penile tumescence,16, 17 suggesting that depression can directly affect the erectile process. Finally, hormonal changes in the aging male, such as a reduction of circulating testosterone, or cardiovascular disease, may cause both conditions, or alternatively, both conditions can coexist but be etiologically unrelated.
Both major depressive disorder and milder depressive syndromes are characterized by a pervasive low mood and/or loss of interest in daily activities, and little is known about the possible relation between mood disturbances and QoL.18 Few studies on the relation between ED and QoL have controlled for the potential mediating effects of mood and other variables. Thus, it is possible that ED may impact QoL indirectly through the effects of mood or other psychosocial mediators, such as partner or family relationships.
Numerous clinical trials have demonstrated that ED can be successfully treated in men with comorbid depression, whether or not they are taking concomitant antidepressant medications, resulting in a subsequent improvement in QoL.19, 20, 21, 22, 23 For example, a recent study by our group showed strong effects of ED therapy (drug or placebo) on concomitant mood and QoL changes.23 Of 152 men diagnosed with ED and mild depression and randomized to sildenafil or placebo, 42% were classified as treatment responsive (ie, met defined criteria), and 58% were treatment nonresponsive. Of those men defined as responders, 73% received sildenafil compared with 14% receiving placebo. Hamilton Depression Rating Scale (HDRS) and Beck Depression Index (BDI) scores were significantly improved among treatment-responsive subjects, irrespective of whether they received sildenafil or placebo. These effects were comparable with the beneficial mood effects usually observed in trials of antidepressant therapy.14 For purposes of the present study, we evaluated the relation among sexual function, depression, and QoL before and after treatment in these same patients using a variety of statistical procedures. The overall goal was to develop a conceptual model of the causal relation among these variables and to test the strength of this model by means of path analytical procedures.
Material and methods
This was a retrospective analysis of a multicenter, 12-week, randomized, double-blind, placebo-controlled, flexible-dose study.12 The study was conducted at 20 urology clinics in the United States, each of which had a dual specialty team consisting of a urologist and a psychiatrist. Men with a primary complaint of ED completed the Center for Epidemiologic Studies Depression (CES-D) Scale and were offered an appointment with the study psychiatrist if their CES-D Scale score was ≥16, the standard screening threshold for depressive illness. Institutional review boards at each center reviewed and approved the protocol, and all men gave written informed consent. Men with ED and mild-to-moderate depression were randomly assigned to receive sildenafil 50 mg or matching placebo. This dose could be adjusted to 100 or 25 mg, based on efficacy and tolerability. Drug was to be taken approximately 1 h before sexual activity but not more than once daily. At baseline (week 0) and week 12, subjects were assessed by a psychiatrist using the HDRS. In addition, a number of self-report instruments were completed.
The inclusion criteria for this study were as follows: men aged 18 y or older in a stable relationship with a female partner for ≥6 months; a documented diagnosis of ED for ≥6 months; a diagnosis of depressive disorder not otherwise specified, based on an abbreviated Structured Clinical Interview from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition;24 and an HDRS25 score ≥12 at the first and second screening interview.
The exclusion criteria were as follows: presence of another current axis I psychiatric disorder, including substance abuse or dependence; current use of nitrates or antidepressant medication; abnormal serum hormone levels (prolactin, testosterone, thyroid); and a history of major hematologic, renal, or hepatic abnormalities, uncontrolled diabetes, retinitis pigmentosa, or serious cardiovascular disease.
Beck Depression Inventory:26 The BDI is a 21-item questionnaire rated on a scale of 0 (minimal) to 3 (severe).
International Index of Erectile Function (IIEF):27 Individual questions from the IIEF were scored on a scale of 1 (worst response) to 5 (best response), with 0 indicating no sexual activity. The 15 questions are divided into five different domains: EF (Q1–5, 15), intercourse satisfaction (Q6–8), orgasmic function (Q9–10), sexual desire (Q11–12), and overall satisfaction (Q13, 14).
Global Efficacy Questions: ‘Did treatment improve your erections?’ and ‘Did treatment improve your ability to have sexual intercourse?’ A priori criteria for identifying treatment-responsive individuals were a response of ‘yes’ to both GEQs and a score of ≥22 on the EF domain of the IIEF at the end of treatment, which indicates no or minimal ED.28
Life Satisfaction Checklist (LSC):29 The eight-item LSC is a measure of life satisfaction that includes questions on life as a whole (Q1), sexual life (Q2) and partner relationships (Q3), social relationships with family (Q4) and friends (Q5), and satisfaction with leisure life (Q6), vocation (Q7), and finances (Q8). Categorical responses range from 1 (‘very dissatisfying’) to 6 (‘very satisfying’).
Statistical analyses were carried out in a series of stages, beginning with the construction of a correlational matrix for the relation between variables at baseline and end of treatment. Initially, separate Pearson's correlation coefficients were calculated to examine the associations among QoL (as determined using questions from the LSC), the EF domain, and mood measurements (as determined using the BDI) at baseline and end of treatment (week 12), and for change from baseline. As a result, six highly associated variables (change from baseline) were selected for further analyses: QoL Q1–4, the EF domain score, and the BDI (mood) total score.
Subsequently, the effects of sildenafil treatment or placebo on EF (IIEF, GEQ), mood (BDI), and QoL (LSC) measures were examined using analysis of covariance (IIEF, BDI, LSC) or logistic regression (GEQs), with age, smoking status, duration of ED, etiology of ED, and baseline score as covariates. Least-squares mean scores were adjusted for the value of covariates.
A series of multiple regression analyses that controlled for age, duration of ED, and treatment group were performed on the change scores to determine the direct and mediational linkages among those variables that constitute the path analysis model. Based on results of previous studies, it was hypothesized that the mood variable was mediating the relation between EF and QoL.
Finally, a causal model was tested and developed using path analysis.30 Causal modeling, using either path analysis or structural equation modeling, is a conceptual and statistical approach for examining the relation between key predictor variables (eg, age, duration of illness) and the mediating or intervening effect on either variables (eg, relationship satisfaction, depression) or more distal and remote outcomes (overall life satisfaction). Our analysis was performed using observable (manifest) variables only, that is, without the inclusion of latent (nonobservable) variables in the model. The relation (or path) between changes in QoL Q1–4 was examined first, and then the paths were expanded by adding the remaining variables one by one until the whole path model was completed. In the regression analysis, the dependent variable was the criterion variable led by all the independent variables (predictors or mediators). Each path relation was based on the beta coefficient of the corresponding independent variable in the regression equation. A mediational relation occurred when a predictor led to the mediator and the mediator led to the criterion variable in a significant manner, as tested using Sobel's t-ratio (Figure 1).31, 32 The model developed here is intended to provide a conceptual framework for further studies evaluating the effects of ED and ED treatments on QoL.
Baseline correlations among ED, mood, and QoL
A previous report established the safety and efficacy of treating ED in men with concomitant mild-to-moderate depression.12 A significant improvement in ED was associated with significant improvement in depression, regardless of treatment (ie, sildenafil or placebo). Similarly, significant effects were noted in treatment responders compared with nonresponders in overall life satisfaction (LSC Q1), sexual life (LSC Q2), and partner relationship (LSC Q4; Table 1). There were significant correlations at baseline between measures of mood and overall satisfaction (Pearson's coefficient r=0.62; P<0.0001) and between mood and EF (r=0.22; P<0.0001), and there was a trend for a correlation between EF and overall life satisfaction (r=0.16; P=0.055; Table 2). Ratings of the partner relationship were highly correlated with family life satisfaction at baseline (r=0.57; P<0.0001), whereas a nonsignificant trend toward a positive association between partner relationship and sexual life satisfaction were observed at baseline (r=0.12; P=0.15). Additional correlations of note at baseline are correlations between mood and sexual QoL (r=0.28; P=0.0004) and mood and partner relationship (r=0.34; P<0.0001).
Treatment effects on correlations of ED, mood, and life satisfaction
Marked treatment effects were observed after 12 weeks on all three parameters, with significant interactions between change scores for mood and life satisfaction (Pearson's coefficient r=0.68), mood and EF (r=0.48), and EF and life satisfaction (r=0.37; P<0.0001 for all 3; Table 2). Additional correlations of note following treatment were those between partner relationship and sexual life satisfaction (r=0.43; P<0.0001), and partner relationship and mood (r=0.48; P<0.0001).
Change score correlations and multivariate analyses
Path analysis of change scores following treatment demonstrated that EF changes were associated with improved mood (P<0.0001). and quality of sexual life (Q2; P<0.0001), which led to improved partner satisfaction (Q3; P<0.0001), family life (Q4; P=0.0014), and overall life satisfaction (Q1; P<0.0001; Figure 2).
Final path model for change from baseline variables
Change in overall life satisfaction (Q1) was the criterion variable because it was highly correlated to other QoL questions. For example, changes in Q2 (sexual life), Q3 (partner satisfaction), and Q4 (family life) were significantly linked to change in Q1 (overall satisfaction) when regressed separately. In addition, changes in sexual life were linked significantly to changes in partner satisfaction. Sobel's t-ratio further indicated that changes in partner satisfaction mediated the relation between overall satisfaction and satisfaction with sexual life (t=2.10, P=0.018). Similarly, changes in satisfaction with family life were related directly to changes in overall satisfaction and also mediated by partner satisfaction (t=2.22, P=0.013). Changes in mood directly precipitated both changes in sexual life and family life satisfaction, and furthermore mediated the pathway from change in EF domain score to change in sexual life satisfaction (t=3.74, P<0.0001; Figure 2).
Increasing evidence from multiple sources has shown a deleterious effect of ED on life satisfaction and overall QoL.4, 5, 29 Despite the lack of standardization and adequate disease-specific, health-related QoL measures, in addition to design and methodological weaknesses in most studies, patients with ED of broad-spectrum etiology consistently show reduced life satisfaction compared with age-matched controls.20, 22 These effects have also been observed in patients with ED and spinal cord injury,33 depression,23 and multiple sclerosis.34 In the current study, we were able to demonstrate a strong negative association at baseline between EF and overall life satisfaction in patients with ED and mild-to-moderate or subsyndromal depression. ED was also strongly correlated with BDI score. Additional baseline correlations showed that satisfaction in the partner relationship was strongly related to family life satisfaction and mood, and that sexual life satisfaction and mood were strongly correlated.
Conversely, beneficial effects of ED therapies on health-related QoL could be explained by several mechanisms. For example, changes in life satisfaction might be a consequence of improved partner relationships; positive changes in sexual confidence, self-concept, or mood; or other nonspecific effects of treatment. Using multiple regression and path analytic procedures in the current study, we tested the validity of a new theoretical model to account for this relation in patients with ED and mild-to-moderate depression. Based on this model, we hypothesized that patients whose mood and overall sexual functioning are improved following ED treatment are likely to experience greater satisfaction in their partner relationship and family life, in general, and that these changes will be associated with positive changes in overall life satisfaction. We have shown that both mood changes and changes in partner relationship and family life satisfaction functioning are predictive of improvements in overall life satisfaction. The model also implies that overall life satisfaction can be conceptualized as the end point or distal consequence of a cascade of intervening psychological or interpersonal benefits of ED treatment, such as improved overall sexual satisfaction, partner, and other family relationships.
Some limitations of the current study warrant consideration. First, the inclusion criteria required that all patients had to have mild-to-moderate depression in addition to ED. Given the presence of disturbed mood in these patients before treatment, and the significant effects of treatment on depression ratings in this study, it is not surprising that mood was a significant mediating variable.23 Theoretically, this relation might be predicted to be even stronger in patients with higher levels of mood disturbance (eg, major depression) and possibly weaker in patients with little or no mood disturbance. Alternatively, because depression is a strong correlate of ED overall,2, 4, 18 the model presented here may be applicable to a significant proportion of the overall population of patients with ED.
We developed our model based solely on a retrospective analysis of data from a previously published study.23 The robustness or predictive validity of the model remains to be demonstrated in further prospective studies. Our model predicts that patients who show less improvement in mood, or whose improvements in sexual function are not associated with positive changes in family or partner relationships, would be less likely to show overall life satisfaction changes following treatment. Conversely, our model implies that ED treatments that combine couples psychotherapy with pharmacological interventions might lead to even greater improvements in life satisfaction as a result of improved interpersonal relationships. These hypotheses remain to be evaluated in further prospective studies.
Use of this model could help identify and explain psychosocial outcomes of ED therapy. By considering the mechanisms involved, clinicians can optimize the overall clinical impact of ED treatment.
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Rosen, R., Seidman, S., Menza, M. et al. Quality of life, mood, and sexual function: a path analytic model of treatment effects in men with erectile dysfunction and depressive symptoms. Int J Impot Res 16, 334–340 (2004). https://doi.org/10.1038/sj.ijir.3901197
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