Effects of Daily Low-Dose PDE5 Treatment in ED Patients
Effects of Daily Low-Dose PDE5 Treatment in ED Patients
Our study demonstrated that daily dosing with udenafil seems to improve general cognition, depression and somatization in patients with ED. When compared with patients receiving placebo, patients with udenafil treatment showed improvements in cognition, depression and somatization, as well as erectile function. Furthermore, improvements in erectile function correlated with improvements in depression, general cognition and frontal executive function.
In our pilot study, we proposed three possible mechanisms by which udenafil improves general cognition and somatization in patients with ED. First, PDE5 inhibitors are believed to enhance memory and learning via facilitation of long-term potentiation mediated by the glutamate-NO-cGMP intracellular pathway, as cGMP-activated protein kinase is thought to mediate memory consolidation via phosphorylation and protein formation. Second, cGMP is a known vasodilator, and the effects of PDE inhibition on cognitive function could be explained by enhancement of cerebrovascular function because of the delivery of glucose and oxygen to the brain. Third, taking a PDE5 inhibitor improves erections, which ameliorates depression or performance anxiety, enhances self-confidence, and thus promotes improved cognition and general health. In a rodent stroke model, several studies have shown that sildenafil treatment increased concentration of vascular endothelial growth factor in the ischemic boundary and substantially increased neovascularization. Another recent in vivo study presented potential functional benefits from sildenafil treatment in a patient with longstanding spastic quadriplegia and suggested that the activity of sildenafil on cerebral neovascularization and neurogenesis may be the mechanism responsible for the beneficial effects. Although our study was conducted in healthy volunteers without brain lesions, in addition to the three previously mentioned possible mechanisms, we must also consider that PDE5 inhibitors may promote cerebral neovascularization and neurogenesis mediated by the glutamate-NO-cGMP intracellular pathway.
Only a few studies have investigated the association between PDE5 inhibitors and cerebral blood flow. There have been several studies supporting the role of PDE5 inhibitors in increasing cerebral blood flow, although there is still some debate regarding this role. Measurement of changes in cerebral artery blood flow velocity would allow for a more definite conclusion regarding the effects of PDE5 inhibitors on cerebral blood flow.
There is an increasing body of evidence to support the concept that feelings of depression in patients with ED may be resolved with optimal ED therapy. Hatzichristou et al. demonstrated that symptoms of depression were statistically reduced in a vardenafil treatment group compared with a placebo group, and significantly more patients in the vardenafil treatment group reported an improvement in self-confidence. Another study demonstrated that significant improvements in erectile function and depression occurred in patients treated with vardenafil compared with placebo. Treatment of ED should be considered a component of therapy for men with depression and ED.
The improvement of cognitive function, especially frontal executive function, may be closely linked to improvements in depression and self-confidence, but there are several different views on how cognitive dysfunction and depression are related. A classical viewpoint is that cognitive deficits are a net result of depression. Regardless of the cause, cognitive dysfunctions in depression appear to be common and can be measured using a series of cognitive tests. However, a bidirectional relationship between cognition and depression has been suggested in anecdotal studies. Another consideration would be that the results may have been influenced by several hidden clinical factors such as amelioration of anxiety or performance anxiety over the study period.
A strong correlation has been observed between improved erections and improvement of depression and frontal lobe function. Little is known about the exact mechanisms, but a possible mechanism is that significant differences exist among patients in the distribution and number of PDE5 receptors in the erectile bodies and brain. In addition, as erectile function improved, there was a corresponding improvement in depressive symptoms and self-confidence, which might have an effect on cognitive function. We have also observed that patients showed improvements in K-MMSE for general cognition after udenafil therapy. However, there was no improvement in SVLT for verbal episodic memory and learning in the present study. This demonstrates that cognitive domains other than verbal episodic memory may be improved, which may have resulted in the improvement in K-MMSE score, which is representative of general cognition. Along with the improvement of erectile function, there were also improvements in depression, general cognition and frontal executive. Therefore, we suggest that udenafil might improve depressive symptoms, frontal executive function and general cognition, although episodic memory, a clinical hallmark of degenerative dementia such as Alzheimer's disease, was not affected.
Cognitive effects have been demonstrated in animal studies with single and repeated dosing of PDE5 inhibitors. However, in a placebo-controlled 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 cognitive function. It was suggested that the doses used were not optimal and that repeated dosing with sildenafil may be required to produce cognitive and behavioral effects. Accordingly, in both the previous study and our current study, repeated or daily low-dose udenafil seemed to be effective in enhancing cognitive function.
Despite the generally favorable results of our study, there were some limitations that should be addressed. First, the significant improvement of K-MMSE, PHQ-9 and PHQ-15 total score after treatment should be interpreted with caution, as the magnitude of improvement in each rating scale was only 1–2 points (1.25, −2.04 and −2.17 from baseline to the end of treatment in the udenafil group, respectively). Although the differences were statistically significant between the two groups, the clinical relevance is limited, as there is no evidence to suggest substantial improvement in clinical symptoms with test score differences of only 1–2 points. Second, we conducted this study in healthy volunteers without cognitive deficits and other psychiatric disorders, and this point should be reflected in the interpretation of the results. Given that all patients had to have a female partner to be included, the sample results are also limited to behaviorally heterosexual men. Third, our findings were based on a relatively short duration of treatment (8 weeks) and a small sample size. Finally, our multiple comparisons for the outcome should have statistical adjustment such as Boferroni correction, however, such statistical correction may have some shortcomings such as increasing rates of type II error and publication bias. Furthermore, most of our results still remained statistically significant even after adjusting for factors for corrections, which might have reflected those alpha levels achieved in our study. Such multiple comparison issues should be also kept in mind in interpretation of our results. Regarding the sample size issue, the effect size detected in our study was 0.8, corresponding to a large Cohen's d based on the change in IIEF-5 during the study despite of small sample size. Considering the study limitations, a long-term, multicenter trial should be performed to further determine the effects of udenafil on cognitive function, depression and somatization in patients with ED. Although improvements in general cognition and somatization were demonstrated, we cannot provide a clear mechanism for this change. Therefore, the measurement of cerebral blood flow and cerebral metabolism with comprehensive neuropsychometric assessments is essential to determine the precise mechanisms of the cognitive-enhancing effects of PDE5 inhibitors in humans.
In conclusion, daily dosing with a PDE5 inhibitor seems to improve cognitive function, depression and somatization, as well as erectile function, without adverse side effects in patients with ED. In particular, improvement in ED correlated with improvements in general cognitive function, frontal lobe function and depression. Although we obtained positive findings, we cannot provide a clear physiologic mechanism. Therefore, the measurement of cerebral blood flow and cerebral metabolism with comprehensive neuropsychometric assessment is essential to determine the precise mechanisms of the cognitive-enhancing effects of PDE5 inhibitors in humans.
Discussion
Our study demonstrated that daily dosing with udenafil seems to improve general cognition, depression and somatization in patients with ED. When compared with patients receiving placebo, patients with udenafil treatment showed improvements in cognition, depression and somatization, as well as erectile function. Furthermore, improvements in erectile function correlated with improvements in depression, general cognition and frontal executive function.
In our pilot study, we proposed three possible mechanisms by which udenafil improves general cognition and somatization in patients with ED. First, PDE5 inhibitors are believed to enhance memory and learning via facilitation of long-term potentiation mediated by the glutamate-NO-cGMP intracellular pathway, as cGMP-activated protein kinase is thought to mediate memory consolidation via phosphorylation and protein formation. Second, cGMP is a known vasodilator, and the effects of PDE inhibition on cognitive function could be explained by enhancement of cerebrovascular function because of the delivery of glucose and oxygen to the brain. Third, taking a PDE5 inhibitor improves erections, which ameliorates depression or performance anxiety, enhances self-confidence, and thus promotes improved cognition and general health. In a rodent stroke model, several studies have shown that sildenafil treatment increased concentration of vascular endothelial growth factor in the ischemic boundary and substantially increased neovascularization. Another recent in vivo study presented potential functional benefits from sildenafil treatment in a patient with longstanding spastic quadriplegia and suggested that the activity of sildenafil on cerebral neovascularization and neurogenesis may be the mechanism responsible for the beneficial effects. Although our study was conducted in healthy volunteers without brain lesions, in addition to the three previously mentioned possible mechanisms, we must also consider that PDE5 inhibitors may promote cerebral neovascularization and neurogenesis mediated by the glutamate-NO-cGMP intracellular pathway.
Only a few studies have investigated the association between PDE5 inhibitors and cerebral blood flow. There have been several studies supporting the role of PDE5 inhibitors in increasing cerebral blood flow, although there is still some debate regarding this role. Measurement of changes in cerebral artery blood flow velocity would allow for a more definite conclusion regarding the effects of PDE5 inhibitors on cerebral blood flow.
There is an increasing body of evidence to support the concept that feelings of depression in patients with ED may be resolved with optimal ED therapy. Hatzichristou et al. demonstrated that symptoms of depression were statistically reduced in a vardenafil treatment group compared with a placebo group, and significantly more patients in the vardenafil treatment group reported an improvement in self-confidence. Another study demonstrated that significant improvements in erectile function and depression occurred in patients treated with vardenafil compared with placebo. Treatment of ED should be considered a component of therapy for men with depression and ED.
The improvement of cognitive function, especially frontal executive function, may be closely linked to improvements in depression and self-confidence, but there are several different views on how cognitive dysfunction and depression are related. A classical viewpoint is that cognitive deficits are a net result of depression. Regardless of the cause, cognitive dysfunctions in depression appear to be common and can be measured using a series of cognitive tests. However, a bidirectional relationship between cognition and depression has been suggested in anecdotal studies. Another consideration would be that the results may have been influenced by several hidden clinical factors such as amelioration of anxiety or performance anxiety over the study period.
A strong correlation has been observed between improved erections and improvement of depression and frontal lobe function. Little is known about the exact mechanisms, but a possible mechanism is that significant differences exist among patients in the distribution and number of PDE5 receptors in the erectile bodies and brain. In addition, as erectile function improved, there was a corresponding improvement in depressive symptoms and self-confidence, which might have an effect on cognitive function. We have also observed that patients showed improvements in K-MMSE for general cognition after udenafil therapy. However, there was no improvement in SVLT for verbal episodic memory and learning in the present study. This demonstrates that cognitive domains other than verbal episodic memory may be improved, which may have resulted in the improvement in K-MMSE score, which is representative of general cognition. Along with the improvement of erectile function, there were also improvements in depression, general cognition and frontal executive. Therefore, we suggest that udenafil might improve depressive symptoms, frontal executive function and general cognition, although episodic memory, a clinical hallmark of degenerative dementia such as Alzheimer's disease, was not affected.
Cognitive effects have been demonstrated in animal studies with single and repeated dosing of PDE5 inhibitors. However, in a placebo-controlled 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 cognitive function. It was suggested that the doses used were not optimal and that repeated dosing with sildenafil may be required to produce cognitive and behavioral effects. Accordingly, in both the previous study and our current study, repeated or daily low-dose udenafil seemed to be effective in enhancing cognitive function.
Despite the generally favorable results of our study, there were some limitations that should be addressed. First, the significant improvement of K-MMSE, PHQ-9 and PHQ-15 total score after treatment should be interpreted with caution, as the magnitude of improvement in each rating scale was only 1–2 points (1.25, −2.04 and −2.17 from baseline to the end of treatment in the udenafil group, respectively). Although the differences were statistically significant between the two groups, the clinical relevance is limited, as there is no evidence to suggest substantial improvement in clinical symptoms with test score differences of only 1–2 points. Second, we conducted this study in healthy volunteers without cognitive deficits and other psychiatric disorders, and this point should be reflected in the interpretation of the results. Given that all patients had to have a female partner to be included, the sample results are also limited to behaviorally heterosexual men. Third, our findings were based on a relatively short duration of treatment (8 weeks) and a small sample size. Finally, our multiple comparisons for the outcome should have statistical adjustment such as Boferroni correction, however, such statistical correction may have some shortcomings such as increasing rates of type II error and publication bias. Furthermore, most of our results still remained statistically significant even after adjusting for factors for corrections, which might have reflected those alpha levels achieved in our study. Such multiple comparison issues should be also kept in mind in interpretation of our results. Regarding the sample size issue, the effect size detected in our study was 0.8, corresponding to a large Cohen's d based on the change in IIEF-5 during the study despite of small sample size. Considering the study limitations, a long-term, multicenter trial should be performed to further determine the effects of udenafil on cognitive function, depression and somatization in patients with ED. Although improvements in general cognition and somatization were demonstrated, we cannot provide a clear mechanism for this change. Therefore, the measurement of cerebral blood flow and cerebral metabolism with comprehensive neuropsychometric assessments is essential to determine the precise mechanisms of the cognitive-enhancing effects of PDE5 inhibitors in humans.
In conclusion, daily dosing with a PDE5 inhibitor seems to improve cognitive function, depression and somatization, as well as erectile function, without adverse side effects in patients with ED. In particular, improvement in ED correlated with improvements in general cognitive function, frontal lobe function and depression. Although we obtained positive findings, we cannot provide a clear physiologic mechanism. Therefore, the measurement of cerebral blood flow and cerebral metabolism with comprehensive neuropsychometric assessment is essential to determine the precise mechanisms of the cognitive-enhancing effects of PDE5 inhibitors in humans.