Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression

CONTEXT: Genetic moderation of the depression-inducing effects of stressful life events (SLEs) has been reported, but findings suggest that genes may not moderate the effects of SLEs per se but instead may moderate the risk of depression associated with the stable tendency to develop negative emotions in response to minor environmental experiences. OBJECTIVE: To examine whether a functional polymorphism of the serotonin transporter gene (5-HTTLPR) moderates the association between negative affectivity (neuroticism) and depression and to what degree this can explain previous findings involving SLEs. DESIGN: A prospective cohort study involving 1 baseline and 4 follow-up measurements in 15 months analyzing change in self-reported depressive symptoms across time as a function of negatively attributed SLEs, neuroticism, 5-HTTLPR, and their interactions. SETTING: General community. PARTICIPANTS: A population-based sample of 374 ethnically homogeneous young adult female twins. MAIN OUTCOME MEASURE: A continuous score of self-reported depressive symptoms. RESULTS: The depressogenic effect of SLEs in the 3 months before interview was significantly greater in women with 2 short (S) alleles compared with women with 1 or none. However, this effect disappeared after accounting for the effect of SLEs conditional on neuroticism. Similarly, the depressogenic effect of neuroticism was progressively greater with number of S alleles, and this was unchanged after accounting for the effect of neuroticism conditional on SLEs. CONCLUSIONS: Genotype x environment interactions in depression may be more productively interpreted by involving mechanisms more proximal to psychological experience itself. The probability that stress-related cognitive vulnerabilities for depression result in symptom formation may be moderated by a neurobiologic phenotype characterized by altered processing of negative emotions associated with variation in 5-HTTLPR.     

Resilience,stressful life events,and depressive symptomatology among older Chinese adults

Objective: The association between exposure to stressful life events (SLEs) and late-life depression is well-documented. However, the role of resilience as a buffer against the adverse mental health effects of SLEs in late life has not been convincingly demonstrated. In this paper, the moderating effect of resilience in the relationship between SLEs and depressive symptomatology in older Chinese adults is investigated.

Method: A population sample of 385 community-dwelling older Chinese adults aged ≥60 years responded to questionnaires on resilience (Connor–Davidson resilience scale), depressive symptomatology (Geriatric Depression Scale, GDS-15) and SLEs.

Results: Increased numbers of SLEs (β = 0.343, p < .001) and lower levels of resilience (β = –0.137, p < 0.001) were significantly associated with higher levels of depressive symptomatology. There was a significant interaction of resilience and number of SLEs on depressive symptomatology (p = 0.003). The sense of personal competence and optimism was the principal underlying resilience dimension moderating the relationship for both the young–old (aged 60–69) and the old–old (aged 70 and above).

Conclusion: The finding of significant interaction supported the role of resilience in moderating the adverse effect of SLEs in terms of depressive symptoms among older Chinese adults.     

C-reactive protein and response to lurasidone treatment in children and adolescents with bipolar I depression: Results from a placebo-controlled trial

This study sought to investigate associations between levels of high-sensitivity c-reactive protein (hsCRP) prior to treatment and change in depressive symptoms and cognition in a short-term, double-blind, placebo-controlled study of lurasidone in children and adolescents with bipolar I depression. Patients 10–17 years of age with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexibly dosed lurasidone (20–80 mg/day) (n = 173) or placebo (n = 170). The primary efficacy measure was change from baseline to week 6 in the Children’s Depression Rating Scale, Revised (CDRS-R). Treatment response was defined as 50% or greater improvement on the CDRS-R from baseline to week 6. Cognitive function was evaluated with the computerized Brief Cogstate Battery at baseline and week 6. Analyses were adjusted for baseline BMI, as well as age. HsCRP was evaluated as a logarithmically transformed continuous variable and as a categorical variable dichotomized into lower (<1 mg/L) and higher (≥1 mg/L) subgroups. A significant interaction was found between baseline hsCRP and treatment group for change in CDRS-R score at study endpoint, with larger placebo-corrected effect sizes for lurasidone in the higher baseline hsCRP group (≥1 mg/L). A significant BMI-by-hsCRP-by-treatment interaction was found for response rate with higher baseline hsCRP levels associated with greater antidepressant response to lurasidone (vs. placebo) in the normal BMI range subgroup (NNT = 2 in higher hsCRP vs. NNT = 5 in lower hsCRP groups) but not in the overweight/obese patients (NNT = 6 in higher hsCRP vs. NNT = 5 in lower hsCRP). Similarly, a significant interaction effect was observed for the combination of hsCRP and BMI on the procognitive effect of lurasidone, with higher baseline hsCRP levels being associated with improvement in cognitive function for lurasidone (vs placebo) in the normal BMI range subgroup but not in overweight/obese patients. These results suggest that young patients with bipolar depression with normal weight and higher levels of pre-treatment CRP may show a greater placebo-adjusted improvement in depressive symptoms and cognitive performance when treated with lurasidone. If these findings are confirmed in future prospective studies, CRP and BMI may prove to be useful diagnostic and predictive biomarkers in the treatment with lurasidone of children and adolescents with bipolar depression.     

Direct and buffering effects of social support on depressive symptoms of the elderly with home help

The purpose of the present study was to examine the prevalence of depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CES-D) and the effect of life stressors or social support on depressive symptoms in 303 elderly people receiving social services at home. We conducted a questionnaire survey six times with a 1-month interval. In the initial wave of questionnaires, 92 (31%) scored 16 points or above on the CES-D, indicative of a risk for depression. Before life stressors, subjects with low-level support showed significantly more severe depressive symptoms than those with high-level support. Subjects with low-level support were significantly more depressive after life stressors than they had been before, whereas those with middle- and high-level support showed no such difference. The former and latter results seem to suggest the direct and buffering effects of social support on depressive symptoms, respectively.     

Improvement in depression associated with partial epilepsy in patients treated with lamotrigine

Interictal depression is common in patients with epilepsy and it significantly impacts quality of life. Previous studies indicate that lamotrigine may have antidepressant properties. Thirteen adults with uncontrolled partial seizures and concomitant depression were evaluated using measures of depression [Montgomery and Asberg Depression Rating Scale (MADRS) and the MMPI Depression Scale] and anxiety [Spielberger's State-Trait Anxiety Inventory (STAI)] to test the effects of lamotrigine on mood. Evaluations after 5 weeks and again after 3 months of lamotrigine treatment demonstrated significant improvement in depression and anxiety. Mean MADRS overall scores were significantly lower than pretreatment baseline at the 5-week and 3-month evaluations. The mean MMPI Depression score was significantly lower than baseline at the 3-month evaluation. State anxiety scores were significantly reduced from baseline after 5 weeks, but not at 3 months, whereas Trait anxiety scores were reduced from baseline at the 5-week and 3-month evaluations.     

Intensive psychosocial intervention enhances functioning in patients with bipolar depression: results from a 9-month randomized controlled trial

OBJECTIVE: Psychosocial interventions are effective adjuncts to pharmacotherapy in delaying recurrences of bipolar disorder; however, to date their effects on life functioning have been given little attention. In a randomized trial, the authors examined the impact of intensive psychosocial treatment plus pharmacotherapy on the functional outcomes of patients with bipolar disorder over the 9 months following a depressive episode. METHOD: Participants were 152 depressed outpatients with bipolar I or bipolar II disorder in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. All patients received pharmacotherapy. Eighty-four patients were randomly assigned to intensive psychosocial intervention (30 sessions over 9 months of interpersonal and social rhythm therapy, cognitive behavior therapy [CBT], or family-focused therapy), and 68 patients were randomly assigned to collaborative care (a 3-session psychoeducational treatment). Independent evaluators rated the four subscales of the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) (relationships, satisfaction with activities, work/role functioning, and recreational activities) through structured interviews given at baseline and every 3 months over a 9-month period. RESULTS: Patients in intensive psychotherapy had better total functioning, relationship functioning, and life satisfaction scores over 9 months than patients in collaborative care, even after pretreatment functioning and concurrent depression scores were covaried. No effects of psychosocial intervention were observed on work/role functioning or recreation scores during this 9-month period. CONCLUSIONS: Intensive psychosocial treatment enhances relationship functioning and life satisfaction among patients with bipolar disorder. Alternate interventions focused on the specific cognitive deficits of individuals with bipolar disorder may be necessary to enhance vocational functioning after a depressive episode.     

Enhanced suppression of adrenocorticotropic hormone and cortisol responses to hypothalamic-pituitary-adrenal function and thyrotropin-releasing hormone tests after stressful life events in patients with major depressive disorder

BACKGROUND: It is commonly believed that there exists a relationship between the outcome of thyrotropin-releasing hormone (TRH) test, the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test and stressful life events (SLEs) in major depressive disorder. OBJECTIVE: SLEs influence the TRH and DEX/CRH tests in major depressive disorder when administered at the time of admission and improvement. Methods: The TRH and DEX/CRH tests were administered to patients hospitalized for major depressive disorders - on the 4th through the 7th hospital day and at the time of improvement. We measured DeltaMAX TSH, DeltaMAX ACTH, ACTH AUC, DeltaMAX cortisol, cortisol AUC, DeltaMAX ACTH/DeltaMAX TSH and DeltaMAX cortisol/DeltaMAX TSH. RESULTS: SLEs were significantly negatively associated with DeltaMAX ACTH, ACTH AUC and cortisol AUC at the time of admission. However, these relationships lost significance at the time of improvement. The sample (41 patients at the time of admission, 18 patients at the time of improvement) was relatively small, which may have contributed to false-negative results. CONCLUSION: SLEs may be negatively associated with the outcome of the DEX/CRH tests in major depressive disorder. The hypothalamic-pituitary-adrenal axis in the DEX/CRH test was modulated by SLEs.     

Life events and onset of a new phase in bipolar affective disorder

Background: There is an increasing focus on the impact of psychosocial factors and stressors on the course of bipolar affective disorder. The life event research has revealed many biases and the results are conflicting. In a prospective study we examined the relationship between life events and affective phases in a group of bipolar patients with a long duration of the disease. Methods: A group of patients with at least three admissions to hospital for bipolar disorder was followed every 3 months for up to 3 years. At each examination an evaluation of affective phase was made according to the Hamilton Depression Scale, the Newcastle Depression Rating Scale and the Bech‐Rafaelsen Mania Rating Scale. Moreover, the patients were rated according to the Paykel Life Events Scale. Their current medical treatment was noted. Results: Fifty‐six patients (19 men and 37 women) were included in the study. Women experienced a significantly higher number of life events than men. In 21% of the 353 examinations of women, a new phase was preceded by life events whereas this was the case only in 8% of the 152 examinations of men. In 13% of the male examinations the patients were in a manic phase and in 5% in a depressive phase. In 5% of the female examinations the patients were in a manic phase and in 15% in a depressive phase. Half of the women's depressive phases were preceded by life events, but none of the depressive phases of men. The categories of life events preceding the depressive phases presented a significant overweight of somatic ill health and conflicts in the family. Conclusion: We found a gender difference in the course of bipolar affective disorder, as women had a significantly higher number of depressive episodes than men and men had a higher number of manic episodes than women. In bipolar patients with long duration of disease a significant number of depressive episodes in women were preceded by negative life events. Somatic health problems and conflicts in the family were significant factors preceding new depressive phases.     

The prognostic significance of depressive symptoms for predicting quality of life 12 months after gastric bypass

OBJECTIVE: This study was conducted to examine the relative prognostic significance of weight and depressive symptoms for 12-month postoperative health-related quality of life (HRQL) in extremely obese gastric bypass patients. METHODS: Participants comprised 137 extremely obese patients undergoing gastric bypass surgery. Presurgery and 12 months postsurgery participants completed the Medical Outcomes Study Short Form-36 Health Survey, a standard measure of HRQL, and the Beck Depression Inventory (BDI). Regression analyses were performed to predict HRQL, both before and 12 months after surgery, by using demographic variables, and measures of body mass index (BMI) and depressive symptoms as predictors. RESULTS: At baseline the predictors accounted for 19% of the variance of physical HRQL, and 56% of the variance of mental HRQL. At 12 months after surgery, the predictors accounted for 32% of the variance of physical HRQL and 48% of mental HRQL. In the prediction of 12-month postoperative HRQL, baseline BMI, BMI unit change, baseline BDI, and improvements in BDI score made significant contributions to most of the Medical Outcomes Study Short Form-36 Health Survey scales. Demography contributed little to these predictor analyses. Depressive symptoms made greater contributions than weight and demography, and change in BDI score made the greatest contributions (ranging from 3% to 37%) of all the variables tested. CONCLUSIONS: Measures of weight and depressive symptoms were useful in predicting quality of life both before and 12 months after gastric bypass surgery; however, this is the first study to document that improvements in HRQL postsurgery may be largely related to improved depressive symptoms.     

Psychosocial and neurocognitive functioning in unipolar and bipolar depression: a 12-month prospective study

Previous studies have revealed psychosocial and cognitive impairments in patients during unipolar and bipolar depression, which persist even in subsyndromal and euthymic states. Currently, little is known about the nature and the extent of psychosocial and cognitive deficits during depression. The aim of the present study was to characterize psychosocial and cognitive profiles among unipolar (MDD) and bipolar (BD) patients during a major depressive episode and to compare the profiles of the patient groups. Depressed patients with MDD (n=13) and BD (n=11) were followed over a period of 12 months. Clinical, psychosocial and neuropsychological assessments were conducted at baseline and at 6-week, 4-month, 8-month and 12-month follow-ups. In the case of severe mood disorders, psychosocial and neurocognitive functioning seem similar among MDD and BD patients during a depressive episode. All MDD and BD patients had global psychosocial dysfunction, characterized by occupational and relational impairments. Furthermore, the neurocognitive profile was heterogeneous with regard to the nature and extent of cognitive deficits but attentional processes were frequently compromised. After 1 year of treatment, occupational and relational impairments, as well as neurocognitive dysfunction, persisted sufficiently to alter daily functioning.     

Desipramine treatment of cocaine dependence in methadone-maintained patients.

We performed a double-blind, placebo-controlled, randomized 12-week trial of desipramine hydrochloride treatment of cocaine dependence among methadone-maintained patients. Fifty-nine patients completed the 12-week medication trial (36 received desipramine and 23 received placebo), and 94% were recontacted 1, 3, and 6 months after treatment. There were significantly more dropouts in the desipramine than in the placebo group. Baseline to 12-week comparisons of Addiction Severity Index interview data indicated that both groups showed improvements. At 12 weeks, the desipramine group showed significantly better psychiatric status than the placebo group but did not differ from the placebo group on any of 21 other outcome measures, including cocaine use. During the 12-week medication phase and at the 1-month follow-up evaluation, urine toxicology screenings showed no significant difference between groups, but the placebo group had significantly less cocaine use at both the 3- and 6-month follow-up points. We conclude that desipramine has few benefits with regard to control of cocaine use in this population.     

One-year outcome of low-intensity booster sessions versus care as usual in psychosis patients after a short-term psychoeducational intervention.

OBJECTIVE: In this study we aimed to evaluate long-term effects of a community-based, quality of life oriented psychoeducational intervention for schizophrenia with and without booster sessions. METHOD: One hundred and three outpatients with a diagnosis of schizophrenia or schizoaffective disorder completed a 9-week psychoeducational programme. At the end of the programme groups were block-randomised to either an extension programme comprising monthly booster sessions for a further nine months (booster condition) or routine clinical care with no further group meetings (non-booster condition). Outcome measures were applied before and after the seminar and at 6 and 12 months. RESULTS: Positive effects were observed after the short-term 9-week programme with regard to symptoms, knowledge about the illness, illness concept, control convictions and quality of life. These effects were retained over the 12-month period in both conditions. The only relevant difference between the booster and the non-booster conditions concerned external control convictions. CONCLUSION: Overall this 9-week programme has shown encouraging effects still present at 12 months after baseline independent of booster or non-booster conditions. Further studies are needed to explore whether a subgroup of patients, those with impaired neurocognitive and social functioning, can benefit significantly from booster sessions.     

NGAL and other markers of inflammation as competitive or complementary markers for depressive symptom dimensions in heart failure

Objectives. Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory marker associated with the pathophysiology of heart failure (HF), the psychopathology of depression and the co-existing symptoms of depression in HF patients. The aim of this study is to determine whether the association of serum NGAL levels with depressive symptoms dimensions in HF is independent of well-known inflammatory markers. Methods. Serum NGAL, high sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α), its two soluble receptors; sTNFR1, sTNFR2, Interleukin-6 (IL-6) and leukocytes were measured in 104 patients with HF at baseline and 12 months. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at both timepoints. Correlations between NGAL and inflammatory markers and depressive symptoms dimensions were determined. The effect of hsCRP, IL-6, TNF-α, sTNFR1, sTNFR2 and leukocytes on the association of NGAL with depressive symptoms was determined and adjusted for time, demographics, cardiac disease severity, and kidney function. Results. NGAL levels were significantly correlated with hsCRP, TNF-α, sTNFR1, sTNFR2 and leukocytes. NGAL was significantly associated with somatic depressive symptoms, independent of abovementioned markers. Conclusions. Serum NGAL is an independent inflammatory marker for somatic depressive symptoms in HF and may function as an immunopathogen linking somatic symptoms of depression to HF.     

Randomized, placebo-controlled trial of fluoxetine for acute treatment of minor depressive disorder

OBJECTIVE: Minor depressive disorder is both common and associated with significant psychosocial impairment. This study examined antidepressant treatment efficacy in a large group of patients with minor depressive disorder. METHOD: One hundred sixty-two patients with minor depressive disorder were randomly assigned to receive fluoxetine or placebo in a 12-week, double-blind study; 73% (59 of 81) of the patients in each treatment group completed the study. Patients were evaluated weekly with standard depression rating instruments and measures of psychosocial impairment. Hypotheses were tested by last-observation-carried-forward analysis of variance (ANOVA) and confirmed by mixed (random-effects) regression analysis. RESULTS: At baseline, minor depressive disorder patients were mildly to moderately depressed, with a corresponding degree of functional impairment. Over 12 weeks of treatment, both ANOVA and mixed regression showed fluoxetine to be superior to placebo as indicated by significantly greater improvement of fluoxetine-treated patients in scores on the 30-item clinician-rated Inventory of Depressive Symptomatology, the 17-item and 21-item Hamilton Depression Rating Scale, the Beck Depression Inventory, and the Clinical Global Impression severity scale. Improvement in Global Assessment of Functioning Scale score was significantly greater for the fluoxetine group in mixed regression analysis only. Patients in both treatment groups reported a similar number and severity of adverse events during the 12-week treatment period. CONCLUSIONS: Clinicians frequently encounter minor depressive disorder either as a prodromal or residual phase of illness in major depressive disorder or as de novo minor depressive disorder episodes. Fluoxetine is significantly superior to placebo in reducing minor depressive disorder symptoms within a 12-week period. Improvement in psychosocial function with fluoxetine may take longer than 12 weeks.     

Goal-Directed Fantasy and the Performance of Hypnotic Test Suggestions†

Rejection sensitivity has been found to confer risk for depression. The process through which this occurs remains unclear. This risk factor also has been associated with negative behavioral tendencies and interpersonal difficulties. Drawing on these different lines of research, the current investigation aimed to evaluate stress generation, the tendency for depression-prone individuals to experience higher rates of life stressors that are at least in part influenced by their own behavior, as a potential mechanism mediating the link between rejection sensitivity and subsequent depressive symptoms. Sixty-six adults with a history of depression were followed over a 4-month interval and completed assessments of rejection sensitivity and depressive symptoms at baseline, and depressive symptoms, a diagnostic interview for depression, and a contextual threat life stress interview at 4-month follow-up. Consistent with the stress generation hypothesis, rejection sensitivity predicted higher rates of dependent stressors, but not independent ones, over the 4-month prospective follow-up period. Furthermore, prospectively occurring dependent stressors mediated the relationship between baseline rejection sensitivity and depressive symptoms at follow-up. The finding that stress generation may operate as a mediating mechanism underlying the pathway between rejection sensitivity and depression lends preliminary support for the importance of targeting maladaptive behavioral tendencies in rejection-sensitive individuals in clinical settings.     

Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression

OBJECTIVE: Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression. The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder. METHOD: Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a randomized, parallel-group, double-blind, placebo-controlled trial of lithium augmentation during continuation treatment. After a 2-4-week stabilization period following remission, patients were randomly assigned to receive either lithium or placebo for a 4-month period. Antidepressant medication was continued throughout the study. RESULTS: Relapses (including one suicide) occurred in seven (47%) of the 15 patients who received placebo in addition to antidepressants. None (0%) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study. Five of the seven relapsing patients in the placebo group developed a depressive episode, and the other two experienced a manic episode. CONCLUSIONS: Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse. Patients who respond to lithium augmentation should be maintained on lithium augmentation for a minimum of 6 months or even longer.     

The Factors Influencing Depression Endpoints Research (FINDER) study: final results of Italian patients with depression

Background  

Factors Influencing Depression Endpoints Research (FINDER) is a 6-month, prospective, observational study carried out in 12 European countries aimed at investigating health-related quality of life (HRQoL) in outpatients receiving treatment for a first or new depressive episode. The Italian HRQoL data at 6 months is described in this report, and the factors associated with HRQoL changes were determined.     

Influence of the interaction between the serotonin 1A receptor C-1019G polymorphism and negative life stressors on the development of depression

The current study aimed to investigate the interaction between the serotonin 1A receptor gene (HTR1A) C-1019G polymorphism and recent negative life stressors on depression in a Korean community sample. The HTR1A C-1019G polymorphism was genotyped in 416 community-dwelling Koreans (156 males, 260 females; 44.37 ± 14.67 years old). Lifetime and current major depressive episodes were diagnosed using the Structured Clinical Interview for DSM-IV. The Center for Epidemiological Studies for Depression Scale (CES-D) was self-applied and face-to-face interviews investigating negative life stressors within the last 6 months were also performed. The results indicated that there were significant interactions between the C-1019G polymorphism and negative life stressors on CES-D scores (p = 0.02) as well as on current major depressive episodes (p = 0.002), but not on past major depressive episodes. G carriers alone had higher CES-D scores and more frequently experienced major depressive episodes after stressors. The interaction between the C-1019G polymorphism in HTR1A and recent negative life stressors accounted for current major depressive episodes and depressive symptoms. Our findings suggest that people with this gene variant may be more susceptible to developing depression especially after negative life stressors.     

Change in Attitude Toward Electroconvulsive Therapy: Effects of Treatment, Time Since Treatment, and Severity of Depression

Attitudes toward electroconvulsive therapy (ECT) of patients with major depressive episodes who are treated with ECT were evaluated before the beginning of treatment, 1 to 2 days after completion of the 12th treatment, and 6 months after the termination of the series using a questionnaire (adapted from Freeman and Kendall, 1980). Attitudes toward ECT become more positive after treatment, and remain so at the 6-month follow-up. Attitude changes correlate with changes in depressive symptoms and with subjective side effects during treatment. Patients who had a prior course of ECT had more knowledge of ECT but not a more positive attitude.     

Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate

OBJECTIVE: Depressed men commonly have erectile dysfunction, and men with erectile dysfunction are frequently depressed. Since the etiologic and modulatory relationships between depression and erectile dysfunction have been poorly characterized, a 12-week, randomized, double-blind, placebo-controlled trial was conducted at 20 urologic clinics to evaluate the effects of sildenafil treatment in men with erectile dysfunction and mild-to-moderate comorbid depressive illness. METHOD: Men (N=152, mean age=56 years) with erectile dysfunction for > or =6 months (mean=5.7 years), a DSM-IV diagnosis of depressive disorder not otherwise specified, and a Hamilton Depression Rating Scale score > or =12 (mean at baseline=16.9) were randomly assigned to flexible-dose treatment with sildenafil citrate or matching placebo. Interviewer-rated and self-report instruments were used to assess changes in sexual function, depressive symptoms, and quality of life. Conservative criteria were used to classify erectile dysfunction treatment response and nonresponse. RESULTS: Sildenafil was strongly associated with erectile dysfunction treatment response. Fifty-eight men met the conservative criteria for response (48 given sildenafil, 10 given placebo), and 78 men did not respond (18 given sildenafil, 60 given placebo). Mean decreases of 10.6 and 2.3 in Hamilton depression scale scores were seen in treatment responders and nonresponders, respectively; 76% of treatment responders showed a > or =50% decline in Hamilton depression scale score versus 14% of nonresponders. Quality of life was similarly improved in treatment responders. CONCLUSIONS: Sildenafil is efficacious for erectile dysfunction in men with mild-to-moderate depressive illness. Improvement of erectile dysfunction is associated with marked improvement in depressive symptoms and quality of life.