Problems as to using SSRIs
The efficacies of SSRIs in the treatment of PE have been confirmed for a long time, however, there are some problems needed to be resolved and noted. ¢Ù How to select the kind of drugs? There are many kinds of SSRIs, but only paroxetine, sertraline, fluoxetine and citalopram are effective and widely employed in clinical offices. Paroxetine is the most effective among them and three other drugs have the same efficacies when employed daily.26,30 ¢Ú How to select the dose of drugs? Different doses have been used in different studies. For instance, the dose of paroxetine is commonly 10£40 mg daily, 20 mg on demand 3 to 4 hours prior to intercourse; sertraline 25£100 mg daily, sometimes 200 mg daily, 50 mg on demand 4 to 8 hours prior to intercourse; fluoxetine 5£20 mg daily, sometimes the dose was increased to 40 mg or 60 mg after one week use.8 If the efficacy is not ideal, the dose can be considered to increase because the efficacy is positively related to the dose, but the side-effects also increase with the dose. ¢Û How to select the protocol? There are three protocols of SSRIs to treat PE: taking drugs daily, taking drugs on demand and taking drugs on demand based on the efficacy of taking them daily for a suitable period. How to choose them is not simple. Generally speaking, taking drugs on demand based on the efficacy of taking them daily for a suitable period is the best one among the three protocols because of high efficacy, few side-effects, low expense and natural course based on what is needed.19 All the SSRIs mentioned above can be administrated on demand, however, sertraline is most suitable for using on demand because its special peak plasma level occurs 4 to 8 hours after oral administration, making 5 pm as a suitable time for taking by which time a man may know whether sexual intercourse is likely to occur late in that evening.17 ¢Ü How to select the duration? No universal agreement has been reached on how long SSRIs are employed to treat PE so as to get ideal effect. Recurrence of PE is highly likely to occur following the withdrawal of treatment. Behavior therapy may augment pharmacotherapy to prevent relapse.13 So far, it is unclear and lacks evidence based studies to support that how long the effect can last, how many percents of patients can be cured when SSRIs are administrated, and how many percents of patients will recur after the withdrawal of SSRIs. In addition, there is no clear consensus as to whether SSRIs will be an eventual cure of PE or be required for the whole life. The experience of the AUA erectile dysfunction guideline update panel members is that PE usually returns upon discontinuing therapy.8
Recommendations on using SSRIs
Based on the update data, referenced to some guidelines on therapy to PE,8,12,40,41 and combined with our experiences, the practical recommendations concerning the use of SSRIs in alleviating PE are presented as follows. ¢Ù SSRIs are suggested to be used in young lifelong PE men, while PDE5-Is should be employed in old age or when PE is associated with ED. ¢Ú Etiology-specific treatment and/or behavioral therapy are indicated firstly for acquired PE. When etiological factors are removed but PE still exists, SSRIs are suggested to be employed. ¢Û The protocol of taking drugs on demand based on the efficacy of taking them daily for a suitable period is proposed to be used. ¢Ü When sexual dysfunctions associated with SSRIs occur, particularly ED, PDE5-Is can be administrated to treat them.
Waldinger et al42 formulated a new theory of the cause and genesis of lifelong PE; they postulated that lifelong PE was not an acquired disorder caused by initial hurried intercourse, as suggested by Masters and Johnson. Instead, PE was postulated to be the part of a normal biological variability of IELT in men, with a possible familial genetic vulnerability.42,43 So PE is considered to be primarily a neurobiological phenomenon, which may or may not secondarily cause psychological or psychosocial distress. Male rat studies demonstrated that serotonin 5-HT and 5-HT receptors were involved in the ejaculatory process. As far as is currently known, 5-HT2C and 5-HT1A receptors determine the speed of ejaculation. Stimulating 5-HT2C receptors can delay ejaculation whereas stimulating 5-HT1A receptors can result in shorter ejaculation.40 Based on animal and human psychopharmacological studies, PE is further postulated to be related to the decreased central serotonergic neurotransmission, 5-HT2C receptor hyposensitivity and/or 5-HT1A receptor hypersensitivity.42,44 To understand the suggested biological variation in IELT in relation to the serotonergic system, Waldinger et al45 proposed the existence of a threshold IELT and divided it into three types: low, normal and high. Men with low threshold IELT can sustain only a little sexual arousal before ejaculation and are easy to become PE. The low threshold is assumed to be associated with low serotonergic neurotransmission, 5-HT2C receptor hyposensitivity and/or 5-HT1A receptor hypersensitivity. Men with normal threshold IELT can sustain more sexual arousal before ejaculation and have more control ability over ejaculation. In these men serotonergic neurotransmission varies around a normal or average level and the 5-HT2C receptor functions normally. Men with high threshold IELT may experience difficulty in ejaculation or can not ejaculate even when fully sexual aroused. The high threshold is supposed to be associated with high serotonergic neurotransmission, 5-HT2C receptor hypersensitivity and/or 5-HT1A receptor hyposensitivity. Patients with PE are considered to have low threshold IELT associated with low serotonergic neurotransmission, 5-HT2C receptor hyposensitivity and/or 5-HT1A receptor hypersensitivity. SSRIs can increase serotonergic neurotransmission and activate 5-HT2C receptor, therefore switch the threshold to a higher level and delay ejaculation. This is the main mechanism of SSRIs to treat PE. Stopping treatment results in a uniform resetting of the threshold within 3£5 days to the lower individually determined reference level which is genetically determined, and that is assumed to be the possible mechanism why PE will recur after stopping treatment.
In addition, besides lifelong PE, there are many men with acquired PE caused by psychogenic/relationship factors. Many clinical evidences have demonstrated that PE is associated with lacking of self-esteem, discordant relationship, anxiety, embarrassment and depressed feeling,6,7 which result from PE and then further result in and aggravate PE, just like a cycle. As the drugs to treat depression and anxiety, SSRIs may act via the direct effect of antidepression to alleviate psychogenic PE and therefore break this aggravating cycle.
Yilmaz et al16 reported that 40 patients with PE were divided randomly into study and control groups in a double-blind fashion. The study group was treated with fluoxetine 20 mg daily and the control group with placebo for one month. All the patients were evaluated during visits before and after treatment for IELT, penile sensory threshold values, the variables of sacral evoked response, and cortical somatosensory evoked potential tests. The results demonstrated that at the end of treatment, IELT and penile sensory threshold values were increased in the study group compared with the control group or the baseline. No change was observed in either group for the amplitudes and latencies of sacral evoked response and cortical somatosensory evoked potential tests. These findings suggested that fluoxetine was effective in the treatment of PE partly due to its effect of increasing the penile sensory threshold and decreasing the penile hypersensitivity. Many experimental and clinical researches have proven that patients with PE have penile hypersensitivity,46,47 which may represent an important contributing factor to this condition. The possible mechanisms of SSRIs in the treatment of PE were briefly illustrated as follows: ¢Ù increasing serotonergic neurotransmission and activating 5-HT2C receptor, therefore switching the threshold to a higher level and delaying ejaculation; ¢Ú increasing the penile sensory threshold and decreasing the penile hypersensitivity; ¢Û treating depression and anxiety which result from PE and further result in and aggravate PE.
PDE5-Is act by inhibiting PDE5 hydrolysis of cGMP and then increasing the level of cGMP, which, in turn, cause smooth muscle relaxation. According to the understanding to the pathway of NO-cGMP, which plays a vital role in the relaxation of smooth muscle, the possible mechanisms involved in PDE5-Is enhancing the effectiveness of SSRIs in the combination therapy to PE, can be explained as follows:11,48 relaxing the smooth muscles of vas defense, seminal vesicle, prostate and urethra; prolonging the duration of erection; decreasing the central sympathetic output; and increasing confidence, the perception of ejaculatory control, overall sexual satisfaction, and decreasing the postorgasmic refractory time to achieve a second erection after ejaculation. In addition, PDE5-Is can cure the sexual dysfunction side effects associated with SSRIs, especially ED, maybe also involves in the mechanism which PDE5-Is can enhance the effectiveness of SSRIs in the treatment of PE.
In summary, SSRIs, despite some side effects such as relapse after medication as well as sexual inhibition, are the most commonly employed and have certain efficacies in the treatment of PE via the possible mechanisms of increasing serotonergic neurotransmission and activating 5-HT2C receptor, therefore switching the ejaculatory threshold to a higher level; decreasing the penile sensitivity; and their own effect of antidepression. However, there is no, up to date, any consensus on how to select the kind, dose, protocol and duration of SSRIs. Moreover, owing to the lack of a universally approved definition of PE and a set of agreed measures to assess the efficacies of SSRIs in the treatment of PE, as well as a double-blind, placebo-controlled design with a large number of cases and the IELT assessed by stopwatch, these results can not present sufficiently convincible evidences and maybe have some biases. So, the multiple centers, large sample, double-blind, placebo-controlled and randomized clinical studies need to be performed to elucidate them. The results of dapoxetine phase III studies are extremely encouraging and promising. If further studied and evaluated, it would be the first prescription treatment designed specifically to treat PE.