Effects of Repeated Dosing with Udenafil (Zydena) on Cognition, Somatization and Erection in Patients with Erectile Dysfunction: a Pilot Study

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ORIGINAL ARTICLE Effects of repeated dosing with Udenafil (Zydena) on cognition, somatization and erection in patients with erectile dysfunction: a pilot study

YS Shim1, C-U Pae2,SWKim3, HW Kim4,JCKim5 and JS Koh5

1Department of Neurology, The Catholic University of Korea, Bucheon St. Mary’s Hospital, Bucheon, Korea; 2Department of Psychiatry, The Catholic University of Korea, Bucheon St. Mary’s Hospital, Bucheon, Korea; 3Department of Urology, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea; 4Department of Urology, The Catholic University of Korea, St. Paul’s Hospital, Seoul, Korea and 5Department of Urology, The Catholic University of Korea, Bucheon St. Mary’s Hospital, Bucheon, Korea

The PDE5 inhibitors have recently been found to have cognitive-enhancing effects in animal models. To investigate the efficacy of repeated dosing with a PDE5 inhibitor on cognitive function and somatization in patients with erectile dysfunction, 27 patients with erectile dysfunction received udenafil (100 mg) at 3-day intervals for 2 months. The international index of erectile function-5 (IIEF-5), a cognitive battery (the Korean version of mini-mental state examination (K-MMSE), the frontal assessment battery (K-FAB), the Seoul verbal learning test) and a physical health questionnaire-15 (PHQ-15) were performed at baseline and at 2 months, following the administration of udenafil. The patients were divided on the basis of their IIEF-5 score into responders (change47) and non-responders. The mean IIEF-5 score was significantly increased after treatment (7.92±3.83 to 16.33±4.75, Po0.001). The scores of K-MMSE (27.03±1.58 to 28.07±1.57, P ¼ 0.001), K-FAB (13.65±1.96 to 15.41±1.85, Po0.001) and PHQ-15 (18.92±4.96 to 17.63±4.75, P ¼ 0.003) were significantly improved after treatment. In addition, the responders (n ¼ 16) had more improved cognitive function (r ¼ 0.603, P ¼ 0.001) and somatization (r ¼À0.402, P ¼ 0.038) than non-responders (n ¼ 11). Repeated dosing with a PDE5 inhibitor seems to improve cognitive function and somatization, as well as erectile function in patients with erectile dysfunction. International Journal of Impotence Research (2011) 23, 109–114; doi:10.1038/ijir.2011.13; published online 5 May 2011

Keywords: PDE5 inhibitor; cognition; somatization disorder; erectile dysfunction

Introduction in some countries, such as Korea, Russia, Ukraine and Malaysia, because of the reported safety and Orally administrated PDE5 inhibitors competitively efficacy of udenafil in the treatment of erectile inhibit PDE5, which physiologically inactivates dysfunction.2–4 The PDE5 inhibitors are commonly cyclic guanosine monophosphate (cGMP) in the used for erectile dysfunction, but there have been erectile bodies. Thus, PDE5 inhibitors increase several different attempts to evaluate additional nitric oxide-stimulated cGMP concentration in beneficial effect of PDE5 inhibitors in treatments patients with erectile dysfunction.1 Three PDE5 for pulmonary hypertension,5 benign prostate inhibitors (sildenafil, tadalafil and vardenafil) have hyperplasia6 and stroke.7 been widely used. Udenafil (Zydena), which is the In a recent study, PDE5 has been identified in most recently developed PDE5 inhibitor, is also used the rat brain, including the cortex and hippocampus.8,9 PDE5 inhibitors readily cross the blood–brain barrier and increase cGMP concentra- tions in the intracellular pathway activated by Correspondence: Professor JS Koh, Department of Urology, N-methy-D-aspartic acid receptors, which is be- The Catholic University of Korea, Bucheon St. Mary’s lieved to mediate long-term potentiation and Hospital, 2, Sosadong, Wonmigu, Bucheon, Kyunggido 10–12 420-717, Korea. memory consolidation. Thus, some valuable E-mail: [email protected] animal models have been utilized to confirm the Received 30 November 2010; revised 30 March 2011; cognitive-enhancing effect of PDE5 inhibitors. Sub- accepted 10 April 2011; published online 5 May 2011 chronic administration of sildenafil has been shown Effect of repeated dosing with udenafil on cognition, somatization and erection YS Shim et al 110 to increase cortical cGMP levels13 and sildenafil taking drugs that inhibited or induced hepatic reversed cognitive deficits in rats produced by cytochrome P4503A4, PDE5 inhibitors, nitrates, diabetes,14 anticholinergics15 and hyperammonemia.10 a-blockers, antidepressants or other neuropsychia- Despite positive findings in animal models, in tric medication and (3) patients who were not vivo data are limited and no conclusive remarks can willing to use appropriate methods of contraception be made. There has been only one study, as far as we with their sex partners or patients and their sex know, to investigate the impact of a PDE5 on partners were planning to achieve pregnancy. cognitive function in humans, with a double-blind design along with only a single dose. A single dose of sildenafil (50 or 100 mg) was shown not to have Study design an effect on putative N-methy-D-aspartic acid Thirty-three men who were diagnosed with erectile receptor-mediated memory deficits in schizophrenia dysfunction by clinical history and physical exam- patients. It was suggested that the doses used in the ination were enrolled in this prospective study. study were not optimal and repeated dosing may be After erectile dysfunction had been confirmed, an necessary to achieve therapeutic effects.16 electocardiography was obtained. Patients were Therefore, we conducted this study to assess scheduled for three sessions at 1-month intervals. whether or not repeated dosing with a PDE5 At baseline, we administered the IIEF-5 for erectile inhibitor improves cognitive function and somatiza- dysfunction, physical health questionnaire (PHQ)- tion, as well as erectile function in patients with 15 for somatization and a cognitive battery for erectile dysfunction. cognition. The PHQ–15 is a somatic symptom severity subscale. It assesses 15 somatic symptoms or symptom clusters that account for more than 90% Materials and methods of all physical complaints (excluding upper respira- tory tract symptoms) reported by outpatients. Each The study was conducted at the Clinical Trials item is rated on a scale from 0 to 2. Scoring simply Centre of the Catholic University of Korea. The requires adding the numbers circled, and scores can study protocol was approved by the Institutional range from 0 to 30. The PHQ–15 has already been Review Board. All procedures were performed in validated in primary-care settings.19,20 The cognitive accordance with the recommendation of the battery consisted of the Korean version of the mini- Declaration of Helsinki on biomedical research mental state examination (K-MMSE) for general involving human subjects. All subjects gave written cognitive function,21 the Seoul verbal learning test informed consent before being enrolled. (SVLT) for episodic memory and learning22 and the Korean version of the frontal assessment battery (K-FAB) for frontal executive function.23 The SVLT is the modified Korean version of the Hopkins Subjects verbal learning test,24 and by performing the SVLT, The inclusion criteria were as follows: (1) male scores of three trials and delayed recalls were patients between 40 and 70 years of age, (2) patients recorded for the evaluation of learning and memory who complained of erectile dysfunction for a mini- consolidation. mum of 3 months, (3) patients who had a regular Following the initial baseline evaluation, patients female sex-partner during the study, (4) patients were given udenafil (100 mg) every 3 days for whose international index of erectile function-5 1 month, after which the patients had a follow-up (IIEF-5) score was 21 points on a screening test o evaluation (second visit). This was followed by and (5) patients who did not complain of cognitive an assessment of the IIEF-5 and adverse events. impairment. Erectile dysfunction was defined as an After the assessment, patients were given udenafil inability to attain and/or maintain a penile erection (100 mg) for another month and the IIEF-5, adverse sufficient for satisfactory sexual performance.17 events, the physical health questionnaire-15 The severity of erectile dysfunction was classified (PHQ-15), and cognitive battery were administered based on baseline IIEF erectile function domain (third visit). score into mild (17–21), mild to moderate (12–16), Subjects were divided into two groups (responder moderate (8–11) and severe (5–7).18 The etiology of and non-responder) according to the change in erectile dysfunction was determined by the study IIEF-5 at third visit. Subjects with an increase in investigator based on patient history, as well as the IIEF-5 score (47) were considered to be res- physical and laboratory examination findings. ponders.4 Exclusion to study participation included (1) history of a cerebral vascular accident, myocardial infarc- tion, achromatopsia, dyschromatopsia, retinitis pig- mentosa, head trauma, psychiatric disorder and Statistical analysis dementia (according to DSM-IV or whose MMSE Statistical analyses were performed using the Sta- scores were o24), (2) patients who were currently tistical Package for the Social Sciences (SPSS

International Journal of Impotence Research Effect of repeated dosing with udenafil on cognition, somatization and erection YS Shim et al 111 version 15.0. for Windows; SPSS Inc., Chicago, IL, Table 1 Patients’ demographics and baseline characteristics USA). Continuous data were reported as the mean±s.d. Changes from baseline to the end of Characteristics n ¼ 27 treatment were assessed using the Wilcoxon signed- ± rank test. The age and disease duration distribu- Age (years) 54.81 7.21 Disease duration (months) 33.48±23.70 tions, and the results of baseline evaluations, such as the IIEF-5, PHQ-15, K-MMSE, SVLT, and K-FAB Etiology of erectile dysfunction, n (%) and the changes after treatment, were compared Psychogenic 7 (22.2) between the responder and non-responder groups Organic 13 (48.2) using the Mann–Whitney U-test. Spearman correla- Mixed 8 (29.6) tion analysis was performed for changes in evalua- IIEF erectile function severity, n (%) tion scores of erectile dysfunction, somatization and Mild (17–21) 0 (0) cognitive functions after medication. A 5% level of Mild to moderate (12–16) 4 (14.8) significance was used for all statistical testing. Moderate (8–11) 12 (44.4) Severe (5–7) 11 (40.8)

Underlying disease, n (%) Diabetes mellitus 6 (22.2) Results Hypertension 7 (25.9) Hyperlipidemia 4 (14.8)

Thirty-three patients were enrolled in the study and Abbreviation: IIEF, the international index of erectile function. 27 patients completed the study. One patient dropped out due to hot flushing at second visit and five patients were lost at follow-up (two patients Table 2 Comparative analysis of erection, cognition, and at second visit and three patients at third visit). somatization parameters during follow-up in 27 patients The mean age of the patients who completed the ± Variable At baseline After P-value study was 54.81 7.21 years and the duration of 2 months erectile dysfunction was 33.48±23.70 months. The causes of erectile dysfunction were as follows: IIEF-5 7.92±3.83 16.33±4.75 o0.001 psychogenic etiologies in 7 men (22.2%), organic K-MMSE 27.03±1.58 28.07±1.57 0.001 etiologies in 13 (48.2%) and mixes etiologies in 37 SVLT total recall 14.22±6.89 16.00±6.03 0.075 (29.6%). In severity of erectile dysfunction, 4 men SVLT delayed recall 6.42±2.54 5.92±2.59 0.176 K-FAB 13.65±1.96 15.41±1.85 o0.001 (14.8%) had mild to moderate disease, 12 (44.4%) PHQ-15 18.92±4.96 17.63±4.75 0.003 had moderate disease and 11 (40.8%) had severe disease. Common co-morbid conditions were dia- Abbreviations: IIEF-5, the international index of erectile function-5; betes mellitus, hypertension and hyperlipidemia K-FAB, the Korean version of the frontal assessment battery; (Table 1). After 2 months of treatment, the mean IIEF K-MMSE, the Korean version of the mini-mental state examina- score was significantly increased (from 7.92±3.83 tion; PHQ-15, the physical health questionnaire-15; SVLT, the Seoul verbal learning test. to 16.33±4.75, Po0.001). The K-MMSE (from 27.03±1.58 to 28.07±1.57, P ¼ 0.001), K-FAB (from 13.65±1.96 to 15.41±1.85, Po0.001) and PHQ-15 (Table 3). Correlation analysis showed that the scores (from 18.92±4.96 to 17.63±4.75, P ¼ 0.003) change in IIEF-5 scores correlated with the change were significantly improved after treatment. How- in K-MMSE (r ¼ 0.603, P ¼ 0.001) and PHQ-15 scores ever, there were no differences in the SVLT total and (r ¼À0.402, P ¼ 0.038). delayed recall after treatment (Table 2). Most patients tolerated udenafil therapy well. No Sixteen patients had a change in an IIEF-5 score medication-related severe adverse events were 47 (responder) and 11 patients had the change in an observed, but 2 of 27 patients reported mild diz- IIEF-5 score p7 (non-responder) at the end of ziness. No patients discontinued udenafil therapy. treatment. Age and dysfunction duration were not different between the two groups. The results of baseline evaluations of IIEF-5, K-MMSE, SVLT, K-FAB and PHQ-15 were also not different. After Discussion medication, the mean score changes of IIEF-5 were 10.56±2.65 in the responder group and 5.18±1.60 Several studies have suggested that PDE5 inhibitors in the non-responder group (Po0.001). The results might improve cognition by increasing the concen- of the K-MMSE (responder, 1.56±1.36 versus non- tration of cGMP in rat brains.12–15 However, there responder, 0.27±1.56; P ¼ 0.024) and PHQ-15 has been only one study that has tested the effect of (responder, À2.00±1.75 versus non-responder, PDE5 inhibitor on cognition in human subjects, À0.36 ±2.20; P ¼ 0.042) were different between the especially with psychiatric disorders.16 In contrast two groups. The improvement in the K-MMSE and with anecdotal studies, our study was conducted in PHQ-15 scores were significant in the responders healthy volunteers without psychiatric disorders.

International Journal of Impotence Research Effect of repeated dosing with udenafil on cognition, somatization and erection YS Shim et al 112 Table 3 Patient characteristics and comparative analysis of the and glucose metabolism. Arnavaz et al.26 also mean changes in erection, cognition and somatization parameters reported that neither the intake of sildenafil nor between responders (n ¼ 16) and non-responders (n ¼ 11) during follow-up the application of placebo results in any significant changes in blood flow velocity of the right middle Variable Responders Non-responders P cerebral artery in human subjects. Because we did (n ¼ 16) (n ¼ 11) -value not measure the possible changes in blood flow velocity of cerebral artery, we currently have no Age (years) 53.06±6.49 57.36±7.74 0.131 clinical data to prove whether the PDE5 inhibitors Disease duration 36.00±28.42 29.82±17.47 0.760 can improve cerebral blood flow. However, the (months) improvement in cognitive function observed in the At baseline present study may not likely be associated with IIEF-5 7.12±3.77 9.09±3.78 0.196 increment of blood flow velocity in cerebral vascu- K-MMSE 26.94±1.18 27.18±2.09 0.308 lature based on previous studies. There is an ± ± SVLT total recalls 16.19 7.58 11.36 4.70 0.051 increasing body of evidence to support the concept SVLT delayed 6.63±2.73 5.55±2.30 0.124 recalls that feelings of depression in patients with erectile K-FAB 14.06±1.88 13.55±2.11 0.426 dysfunction may be resolved with optimal erectile PHQ-15 17.81±3.93 20.54±5.98 0.164 dysfunction therapy. Hatzichristou et al.27 demonstrated that the symptoms of depression were statist- Mean changes in IIEF-5 10.56±2.65 5.18±1.60 o0.001 ically reduced in the valdenafil treatment group K-MMSE 1.56±1.36 0.27±1.56 0.024 compared with the placebo group, and significantly SVLT total recalls 0.88±5.54 3.09±5.43 0.143 more patients in the valdenafil treatment group SVLT delayed À0.5±2.85 À0.5±2.27 0.446 reported an improvement in self-confidence. recalls Another study demonstrated that significant im- K-FAB 1.13±1.75 2.18±1.72 0.090 PHQ-15 À2.00±1.75 À0.18±1.83 0.015 provements in erectile function and depression occurred in patients treated with vardenafil versus Abbreviations: IIEF-5, the international index of erectile function- placebo. Treatment of erectile dysfunction should 5; K-FAB, the Korean version of the frontal assessment battery; K- be considered a component of therapy for men MMSE, the Korean version of the mini-mental state examination; with depression and erectile dysfunction.28 In our PHQ-15, the physical health questionnaire-15; SVLT, the Seoul verbal learning test. present study, the improvement of cognitive function may be closely linked to the improvement of depression and self-confidence, but there are different views on how cognitive dysfunction and Our study demonstrated that udenafil seems depression are related. A classical viewpoint is that to improve general cognition and decreases somati- cognitive deficits are a net result of depression. zation in patients with erectile dysfunction, but a Regardless of the cause, cognitive dysfunctions in clear explanation for this positive finding is not depression appear to be common and can be proven known. The possible mechanism by which udenafil with a series of cognitive tests.29 However, we have improves general cognition and decreases somatiza- to consider that a bidirectional relationship between tion in patients with erectile dysfunction may be cognition and depression may have also been that (1) PDE5 inhibitors are believed to enhance proposed in anecdotal studies. Another considera- memory and learning via facilitation of long-term tion would be that all subjects were not blinded to potentiation mediated by the glutamate-nitric oxide- the treatment. Hence, the results might have been cGMP intracellular pathway. The cGMP-activated influenced by several hidden clinical factors such as protein kinase is thought to mediate memory amelioration of anxiety or performance anxiety over consolidation via phosphorylation and protein for- the study period.30 mation. (2) The cGMP is a known vasodilator and Based on an IIEF-5 cutoff score of 7 points, the effects of PDE inhibition on cognitive function patients were divided into two groups, which were could be explained by enhancement of cerebro- the responder and non-responder groups. There was vascular function and the delivery of glucose and a significant difference in the change in cognitive oxygen to the brain. (3) Taking a PDE 5 inhibitor function between the two groups. In the responder improves erection, which ameliorates depression or group, cognitive function significantly improved. anxiety, enhances self-confidence and thus pro- In the current study, an IIEF-5 score of 7 points was motes cognition and general health. set as the cutoff value. To date, in association with There are only a few studies that have investigated the changes in the IIEF score, there is no precise the association between PDE5 inhibitors and cere- definition of ‘responders’ to oral PDE5 inhibitors. bral blood flow. Rutten et al.25 concluded that PDE5 Paick et al.4 conducted a placebo-controlled study inhibitors enhanced memory for objects and loca- involving 167 patients in which they reported that tions by increasing cGMP levels in rodents. How- the mean changes in IIEF-5 scores from baseline ever, this memory-enhancing effect of PDE5 were 7.52 following 12 weeks of udenafil (100 mg). inhibitors is independent of cerebral blood flow Accordingly, we divided patients into the responder

International Journal of Impotence Research Effect of repeated dosing with udenafil on cognition, somatization and erection YS Shim et al 113 and the non-responder groups based on an IIEF-5 addition to the cognitive tests of our study. We score of 7 points. Little is known about the exact examined general cognition, frontal executive func- mechanisms by which cognitive functions further tion, and verbal memory and learning as a pilot increased in the responder group, but the possible study. Based on the present study, we hope further mechanism may be that significant differences in research will be conducted, including more com- the distribution and number of PDE5 receptors in prehensive cognitive assessments. the erectile body and brain between the two groups Although improvement in general cognition and exist. Additionally, as erectile function improved, somatization was demonstrated, we cannot provide there was a corresponding improvement in depres- a clear explanation on the potential mechanisms of sive symptoms and self-confidence, which might this finding. Therefore, the measurement of cerebral have an effect on cognitive function. blood flow and cerebral metabolism with compre- In animal studies, cognitive effects have been hensive neuropsychometric assessments is essential demonstrated with single and repeated dosing of to determine the precise mechanisms of cognitive- PDE5 inhibitors. However, in a placebo-controlled enhancing effects with PDE5 inhibitors in human. study of the effects of sildenafil on cognition in patients with schizophrenia, a single dose of sildenafil (50 or 100 mg) did not have an effect on Conclusion cognitive function.16 It was suggested that the doses Udenafil seems to improve cognitive function and used were not optimal and repeated dosing with somatization, as well as erectile function without sildenafil may be required to produce cognitive and adverse side effects in patients with erectile dys- behavioral effects. Accordingly in the current study, function. In particular, improvement in the IIEF-5 repeated administration of udenafil seemed to be scores correlated with the scores of the MMSE and effective in enhancing cognitive function. Despite PHQ-15. However, our study is based on a relatively the generally favorable results of our study, there small number of patients and a non-randomized were some limitations that should be addressed. design without a placebo group, thus a multicenter, However, significant improvement of K-MMSE and placebo-controlled trial is necessary to determine PHQ-15 total score after treatment should be inter- the effect of repeated dosing with PDE5 inhibitors preted with caution as the magnitude of improve- on cognition and somatization in patients with ment in each rating scale was only one point erectile dysfunction. (4.1 and 6.9% from baseline to the end of treatment, respectively). Although the differences were statis- tically significant, there was a limitation in transla- tion into clinical practice as we had no currently Conflict of interest available evidence that only one point difference may correspond to substantial improvement in The authors declare no conflict of interest. clinical symptoms. 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