Chinese Medical Journal 2011;124(14):2158-2161
Fluoxetine ameliorates symptoms of refractory chronic prostatitis/chronic pelvic pain syndrome

XIA Dan,  WANG Ping,  CHEN Jun,  WANG Shuo,  JIANG Hai

XIA Dan (Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China)

WANG Ping (Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China)

CHEN Jun (Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China)

WANG Shuo (Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China)

JIANG Hai (Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China)

Correspondence to:JIANG Hai,Department of Urology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China (Tel: 86-571-87236282. Fax:. E-mail:jianghaizjueduuro@126.com)
Keywords
chronic prostatitis; chronic pelvic pain syndrome; fluoxetine; quality of life
Abstract
Background  Category III chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common syndrome of unclear etiology with significant impact on quality of life. Because the outcomes of multiple therapies for CP/CPPS have been far from approving, the possible psychological factors have been considered to play an important role in CP/CPPS. Based on this, we investigated the role of antidepressant drug (fluoxetine) in men with refractory CP/CPPS.
Methods  In this study, 42 men diagnosed with refractory CP/CPPS without response to standard therapy (include multiple antibiotic courses and α-blockers) were referred for fluoxetine therapy. All patients received fluoxetine (20 mg/d) for three months and were clinically evaluated before (baseline), and after 4, 8 and 12 weeks of therapy. The evaluation included a National Institutes of Health-chronic prostatitis symptom index (NIH-CPSI) and a Beck depression inventory (BDI) questionnaire. Moreover, the subjective global assessment (SGA) was assessed at the 4th, 8th and 12th week of therapy.
Results  Significant decreases were observed for total NIH-CPSI (28.55 to 9.29), NIH-CPSI pain (14.69 to 5.19), NIH-CPSI urinary (4.95 to 1.88 ), NIH-CPSI quality of life (8.83 to 2.20), and BDI (34.67 to 13.95) scores compared with baseline, all P values <0.05. Twenty-nine (69.05%) reported marked improvement on the subjective global assessment and 33 (78.57%) had a greater than 50% decrease in NIH-CPSI at the end of therapy (12th week). At the same time, the Pearson correlation coefficient analysis demonstrated a positive correlation between BDI score and each CPSI score. No adverse events were reported in this study.
Conclusions  Fluoxetine appears to be a safe and effective treatment in improving symptoms in, and the quality of life of, men with difficult CP/CPPS. Moreover, amelioration of difficult CP/CPPS-related symptoms could be related to a decrease in depressive symptoms.
Chronic prostatitis (CP) is a syndrome in men characterized by pelvic pain with or without voiding symptoms. The vast majority of men with symptomatic prostatitis are category Ⅲ according to the National Institutes of Health (NIH) classification scheme,1 or CP/chronic pelvic pain syndrome (CP/CPPS).
 
The treatment of CP/CPPS can be a frustrating challenge to physicians.2 Since the cause of CP is unknown, its treatment is often unsuccessful. McNaughton Collins et al3 assessed all published randomized or controlled clinical trials for the treatment of chronic abacterial prostatitis in a systematic review and concluded that no treatment approach was currently supported by the available evidence. Patients with CP/CPPS not only have recurrent physical symptoms, but also have many psychological problems. Psychological factor is a common finding in men with CP/CPPS. In an Internet survey, 126 (78%) of 163 patients with CP/CPPS reported minor or major depression, and 8 men (5%) reported suicidal thoughts because of CP/CPPS.4 Because the results of antibiotic therapy for CP/CPPS have been far from convincing, the possible contribution of psychological factors has been considered to play an important role in CP/CPPS.
 
Selective serotonin reuptake inhibitor (SSRI), including fluoxetine, is one of the most widely used antidepressant drugs. In both adults and children with normal intellectual function, fluoxetine effectively ameliorates depression, anxiety, obsessive-compulsive disorder, panic disorder and irritable, difficult temperament. Because of their efficacy for a variety of problems and their safety compared to tricyclics, SSRI drugs are used in millions of patients worldwide.5
 
To further ascertain the possible involvement of psychological factors, such as depression and anxiety, in the etiology of chronic recurrent CP/CPPS in a quantitative manner, the current study investigated the changes of NIH-CPSI and Beck depression inventory (BDI) scores in clinically difficult CP/CPPS patients under treatment with fluoxetine.
 
METHODS
 
This study included 42 consecutive patients who attended our outpatient clinic with a history or symptoms suggestive of CP/CPPS (National Institutes of Health category IIIA and IIIB), with symptoms persisting for at least 6 consecutive months without response to any given therapy (include multiple antibiotic courses and α-blockers). The exclusion criteria were the presence of chronic bacterial prostatitis after a 4-glass lower urinary tract localization test, previous urinary tract infection or a uropathogen documented within the last year, a history of active genital herpes within the previous year, cancer of the genitourinary tract, inflammatory bowel disease, a history of pelvic radiation or systemic chemotherapy, a history of intravesical chemotherapy, active urethral stricture, prostate or bladder surgery and neurologic diseases affecting bladder. All patients underwent a physical examination and standardized process: 4-glass lower urinary tract localization test, semen evaluation (microscopy and culture) and urethral swab test (culture).
 
All patients received fluoxetine (20 mg/d) for three months. All patients were provided written informed consent before the initiation of SSRI (fluoxetine) therapy.
 
The NIH Chronic Prostatitis Symptom Index (NIH-CPSI)6 assessment was completed by each patient at baseline (start of therapy, day 0), 4 weeks, 8 weeks and 12 weeks after the drug therapy. The NIH-CPSI consists of nine questions, exploring the three major domains of prostatitis, i.e. pain (scored 0–21), voiding disturbances (scored 0–10) and quality of life (QOL) impact (scored 0–12); the total NIH-CPSI score is 0–43. Responders were predefined as patients who had experienced a more than 50% decrease in the total NIH-CPSI score.
 
A standard subjective global assessment (SGA)7 was also completed at 4 weeks, 8 weeks, and 12 weeks after the baseline assessment. SGA graded the patient’s improvement as none (≤25% improvement), mild (26%–75% improvement) or marked improvement (>75%). Responders were defined as having a marked (>75%) improvement in their overall symptoms. Moreover, BDI8 was completed by each patient to investigate depressive symptoms. BDI consists of 21 items. Each item has scores ranging from 0 to 3. Thus, the range of possible scores in the BDI is 0–63, and higher scores reflected worse functioning. The degree of depression was assessed according to the following scales: no (0–9); mild (10–15); moderate (16–23) and severe (24–63).
 
The mean values of the total CPSI, pain subscore, urinary subscore, QOL subscore and BDI score were compared on day 0, 4th week, 8th week and 12th week, respectively. Statistical comparison among the groups was performed using one-way analysis of variance (ANOVA), followed by the Tukey test. The Pearson correlation coefficient was analyzed to find correlation between BDI score and each NIH-CPSI score. The criterion for statistical significance was P <0.05. The responder analysis (NIH-CPSI, SGA) data were analyzed descriptively. All statistical analyses were performed using SPSS version 11.0 (SPSS Inc., USA).
 
RESULTS
 
A total of 42 male patients aged (34.5±7.8) years (range 19 to 57 years) were studied. Among these patients, 35.7% were single and 64.3% were married. All patients completed 12 weeks of therapy. None of the patients reported any side effects or problems with fluoxetine therapy.
 
Statistically significant decreases of the mean total CPSI score (28.55 to 9.29), CPSI pain subscore (14.69 to 5.19), CPSI urinary subscore (4.95 to 1.88), and CPSI QOL subscore (8.83 to 2.20) were observed 12 weeks after the baseline assessment and all P values were less than 0.05.
 
Figure shows a box plot of the NIH-CPSI QOL score for patients at baseline and all follow-up phases. Median QOL score decreased to 3 after week 4, and decreased to 2 and achieved a plateau after week 8. The degree of depression was assessed using the BDI. Scores for depression were seen decreasing with decreasing total CPSI score and CPSI subscore. The mean scores for depression were 34.67, 22.60, 14.17, and 13.95 for baseline, the 4th, 8th, and 12th week, respectively (Table).
 

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Figure. Box plot of NIH-CPSI quality of life (QOL) score of men with difficult chronic prostatitis/chronic pelvic pain syndrome who completed treatment with fluoxetine. Bold line represents median score, upper and lower bounds of box 25th and 75th percentiles, respectively, and bars of maximum and minimum scores.
 

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Table. Fluoxetine therapy at different time in 42 men diagnosed with chronic prostatitis/chronic pelvic pain syndrome
 
To investigate the relationship of depression and symptom of CP/CPPS, the Pearson correlation coefficient was analyzed between BDI score and each NIH-CPSI score. We found that a positive correlation between BDI score and total CPSI (P=0.000; r=0.705), pain subscore (P=0.000; r=0.734), urinary subscore (P=0.001; r=0.413), and QOL subscore (P=0.000; r=0.662).
 
After 4 weeks of therapy, 73.81% (31 of 42) of patients were qualified as NIH-CPSI responders (total NIH-CPSI scores drop by 50% or more from baseline), and 59.52% met the criteria of SGA responders (greater than 75% subjective global improvement from baseline). After 8 weeks, these responder numbers increased to 78.57% for NIH-CPSI and 69.05% for SGA, respectively and sustained up to 12 weeks post therapy (Table).
 
DISCUSSION
 
The etiology of CP/CPPS is still unknown. Recent reports have excluded bacteria, obligate anaerobes, fungi, trichomonas, and viruses as pathogenic agents.9,10 Experimental support for the theory that psychological stress may contribute to dysfunction of the prostate was provided by Clark and Treichler,11 who demonstrated that the prostate gland responds to emotional stimulation through the autonomic nervous system. The prostate has autonomic end plates, which have been identified as stress targets. Autonomic fibers have all been found in appropriate sites in prostate.12 Stimulation of the prostate by these fibers results in prostatic fluid secretion and prostatic muscular contraction.
 
Cellular and molecular changes are induced by psychological disorders and/or stress that may have a role in men with CP/CPPS. In comparison to controls, patients with depression have been shown to have lower levels of IL-10 in peripheral blood mononuclear cells than in controls.13 Depression was commonly detected in patients with CP/CPPS.14,15 Egan and Krieger16 reported that 60% of patients with chronic abacterial prostatitis met criteria for a major depression disorder. None was diagnosed as this previously or received medication for depression. Major depression may, therefore, be not recognized in men with this condition.
 
Patients with chronic prostatitis/chronic pelvic pain syndrome not only have recurrent physical symptoms, but also have many psychological problems, including, depression, anxiety, hysteria, hypochondria, and sometimes even suicidal tendencies.17,18 However, to date, no clinical studies have focused on the effect of antidepressive drugs (SSRI, tricyclics) to CP/CPPS. Therefore, to test the theory that antidepressive drugs could relieve the symptom of CP/CPPS, we evaluated the efficacy of fluoxetine, a drug of selective serotonin reuptake inhibitor, in the treatment of patients with difficult CP/CPPS.
 
Serotonin is a key element in the etiology and the therapy of depression and anxiety.19 Stress increases serotonin synthesis, by means of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, and stimulates somatodendritic as well as nerve terminal release of serotonin.20 Fluoxetine is a SSRI used to treat depression which affects serotonin levels in the brain. Tricyclic antidepressants generally are not the first choice for the treatment of depression because of severe side effects, including blurred vision, decreased libido, dizziness, dry mouth, hypertension, increased heart rate, nausea, etc. Therefore, selective SSRI are replacing the place.
 
These 42 men with difficult CP/CPPS demonstrated significant amelioration of chronic prostatitis-related symptoms by fluoxetine. Significant improvements of the average total CPSI score, as well as the separate domains of pain, urinary, and QOL subscores, were observed at as early as the 4th week post initiation of SSRI therapy, and the effects persisted to the end of the study (12th week). More than 70% of patients experienced a greater than 50% decrease in the NIH-CPSI score at 12th week. More than 60% of patients noted a marked improvement on the SGA (patient perceived at least a 75% improvement in subjective symptoms compared with baseline). We also assessed the depression using BDI and found that the BDI score was isochronously decreased with total CPSI score and CPSI subscore. In particular, we found some positive correlations between BDI score and total CPSI, pain subscore, urinary subscore, and QOL subscore. Those results demonstrated that amelioration of difficult CP/CPPS-related symptoms could be related to a decrease in depressive symptoms (BDI score).
 
Our study, which had standardized inclusion/exclusion criteria, and had been followed up using validated outcome parameters assessments, evaluated the potential clinical benefits of fluoxetine in difficult CP/CPPS patients. The data revealed a statistically significant decrease in NIH-CPCI score. The short points of the present study include a relatively small population size and a lack of placebo control group. Despite these limitations, however, the results of the study proved that fluoxetine could provide clinical benefits in terms of symptom amelioration and QOL improvement in refractory CP/CPPS patients, while need further larger, placebo-controlled trials to confirm its effects.
 
Acknowledgments: We would like to thank Dr. MAN Xiao-yong for helping with the statistical analysis.
 
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  1. National Natural Science Foundation of China,No. 30973002;Zhejiang Provincial Natural Science Foundation,No. Y2090099;