An update on the treatment of premature ejaculation: A systematic review

Figures & data

Table 1. The key steps for evaluation of patients with PE

Obtaining the patient’s general medical and sexual history. Classifying PE based on onset (e.g. lifelong or acquired), timing (e.g. prior to or during intercourse), and type (e.g. absolute/generalised or relative/situational). Involving the partner to determine their view of the situation and the impact of PE on the couple as a whole. Identifying sexual comorbidities (e.g. ED) to define whether PE is simple (occurring in the absence of other sexual dysfunctions) or complicated (occurring in the presence of other sexual dysfunctions). Performing physical examination to check the man’s sexual organs and reflexes. Identifying underlying aetiologies and risk factors (e.g. endocrine, urological, or psychorelational/psychosexual) to determine the primary cause of PE and any associated comorbidities. Discussing treatment options to find the most suitable intervention, according to the needs of the man and his partner.

Table 2. The currently available treatment methods for PE

Behavioural therapy	Pharmacological therapy	Surgical therapy
1. Squeeze technique 2. Start/stop technique	1- Non-selective serotonin reuptake inhibitor antidepressants as: Tricyclic antidepressants (Clomipramine). 2- Selective serotonin reuptake inhibitors SSRIs antidepressants such as: a- Fluoxetine b- Citalopram c- Escitalopram d- Sertraline e- Paroxetine f- Fluvoxamine g- Dapoxetine 3- Topical therapy. a. Lidocaine-prilocaine 5% cream b. Local SS cream c. Lidocaine-prilocaine spray d. Dyclonine/alprostadil cream 4- PDE5 inhibitors 5- Opioid agonist. a. Tramadol 6- Others a. Intracorporeal Alprostadil b. Alpha adrenergic blockers c. Folic acid d. Caffeine e. Botulinum toxin injections	1. Glans augmentation 2. Dorsal neurectomy 3. Pulsed radiofrequency neuromodulation 4. Frenectomy 5. Surgical removal of foreskin remnants 6. Varicocelectomy

Figure 1. PRISMA 2009 flow diagram

Table 3. Studies investigating various antidepressants for the treatment of PE

Study	Methods	Intervention	Duration	Sample size	Outcome
Choi et al., 2019 [149]	RCT	Clomipramine 15 mg Placebo	12 weeks	159	Significant increase in IELT in treatment vs placebo, at a mean (SD) of 4.40 (5.29) vs 2.68 (2.03) min (P < 0.05) Significant improvement in PEDT score between both groups (p < 0.001).
Kim et al., 2018 [28]	RCT	Clomipramine 15 mg Clomipramine 30 mg Placebo	4 weeks	101	IELT of both the clomipramine 15 mg group and clomipramine 30 mg group was significantly increased 4 weeks after administration than the placebo group.
Waldinger et al., 2004 [27]	RCT	Clomipramine 25 mg Paroxetine 20 mg	4 weeks	30	Clomipramine led to a 4.05 (95% CI 3.26–5.02) fold-increase of the IELT. Paroxetine led to a 1.41 (95% CI 1.22–1.63) fold-increase of the IELT.
Segraves et al., 1993 [24]	RCT	Clomipramine 25 mg ↑ to 50 mg as needed Placebo	10 coital attempts	20	Average estimated time to ejaculation after vaginal penetration increased to 6.1 min on 25 mg of clomipramine and to 8.4 min on 50 mg of clomipramine.
Strassberg et al 1999., [26]	RCT	Clomipramine 25 mg Placebo	2 weeks	34; 23 with PE and 11 controls received treatment or placebo in 2-week phases	Increase in orgasmic latency in both groups; for PE: from <1 min when taking placebo to 3.5 min when taking clomipramine
Abdel-Hamid et al., 2001 [150]	RCT	Clomipramine 25 mg Sertraline 50 mg Paroxetine 20 mg Sildenafil 50 mg and pause-squeeze technique	4 weeks	31 randomised to receive the 5 treatments followed by 2-week wash-out between treatments.	Median IELT was significantly increased from the pre-treatment median of 1 min to 4, 3, 4, 15 and 3 min during treatment with clomipramine, sertraline, paroxetine, sildenafil and pause-squeeze technique, respectively (all P < 0.001). Sildenafil was superior to other modalities in terms of IELT and satisfaction (P < 0.001). The three antidepressants were comparable to each other in terms of efficacy (P > 0.05).
Jenkins et al., 2019 [47]	POS	Fluoxetine 20 mg	12 months	130	Self-rated ‘poor’ ejaculatory control decreased from 98–41% (P < 0.01), high personal distress from 47–11% (P < 0.01), and high partner distress rates from 72–27% (P < 0.01).
Kara et al., 1996 [46]	RCT	Fluoxetine 20 mg ↑ to 40 mg Placebo	4 weeks	17	The IELT noticeably increased after 4 weeks of treatment with fluoxetine, and patient recordings revealed that improvement began within 1 week of treatment. The mean (SD) intravaginal latency time before treatment was 25 (12.6) s in Group 1 and 30 (8.6) s in Group 2. The mean (SD) IELT increased to 180 (99.5) s in the treatment group (P < 0.05) and 60 (46.9) s in the placebo group (P > 0.05) 4 weeks after beginning treatment.
Manasia et al., 2003 [49]	RCT	Fluoxetine 90 mg/week Fluoxetine 20 mg/day	3 months	80	Mean (range) pre-treatment IELT for groups 1 and 2 was 0.48 (0–2.10) min and 0.50 (0–2.04) min, respectively. After 3 months of treatment of weekly and daily administration of fluoxetine the mean IELT was 3.57 and 3.37 min, respectively (P < 0.01). Partner sexual satisfaction and IIEF rate were greater with 90 mg fluoxetine, but no statistical difference was found.
Siroosbakht et al., 2019 [151]	RCT	Fluoxetine 20 mg Paroxetine 20 mg Citalopram 20 mg Sertraline 50 mg	8 weeks	480	Mean (SD) IELT before, 4 and 8 weeks after treatment in four groups was: sertraline 69.4 (54.3), 353.5 (190.4), 376.3 (143.5) s; fluoxetine 75.5 (64.3), 255.4 (168.2), 314.8 (190.4) s; paroxetine 71.5 (69.1), 320.7 (198.3), 379.9 (154.3) s; citalopram 90.39 (79.3), 279.9 (192.1), 282.5 (171.1) s, respectively. IELT significantly increased in all groups (P < 0.05), but there was no significant difference between the groups (P = 0.75).
Hosseini and Yarmohammadi, 2007 [50]	RCT	Fluoxetine 20 mg Sildenafil 50 mg	4 months	91, Group A: fluoxetine daily for 4 weeks then on demand for 4 months (n = 48) or Group B: same regimen + sildenafil for 4 months (n = 43)	Significant IELT improvement in both groups; Group A, from 0.5 to 4.3 min (P < 0.05); Group B, from 0.55 to 5.1 min (P < 0.005). No differences between both groups.
Mattos et al., 2008 [51]	RCT	Fluoxetine 90 mg Tadalafil 20 mg	4 weeks	90; 4 groups: 1) tadalafil plus fluoxetine, (2) fluoxetine plus placebo, (3) tadalafil plus placebo, and (4) two different placebo capsules (control).	Statistically significant difference in post-treatment IELT was seen with combined treatment compared to placebo (P < 0.001). There were increases in IELT from baseline in patients using fluoxetine plus tadalafil, from a mean (SD) of 49.57 (25.87) to 336.13 (224.77) s (P < 0.001); fluoxetine, from a mean (SD) of 56.55 (18.55) to 233.62 (105.08) s (P < 0.001); and tadalafil, from a mean (SD) of 49.26 (19.43) to 186.53 (159.05) s (P = 0.001).
Madeo et al., 2008 [57]	RCT	Fluoxetine 20 mg Citalopram 20 mg for 1 week then 40 mg Placebo	4 weeks	48	Increase in geometric IELT was observed in the citalopram (3 to 5.9 min), fluoxetine (3.1 to 4.1 min) and placebo groups (3.6 to 3.9 min). The increase was statistically significant in the citalopram group (P = 0.016)
Dadfar and Baghinia, 2010 [58]		Citalopram 20 mg	6 months	16 with failed fluoxetine treatment	The IELT and sexual satisfaction levels both significantly improved after citalopram prescription. The mean (SD) measured IVELT was 0.388 (0.212) min before the treatment, which increased to 4.313 (2.886) min after the treatment.
Kim and Seo, 1998 [152]	RCT	Fluoxetine 40 mg Sertraline 100 mg Clomipramine 50 mg Placebo	4 weeks	36; All patients took each drug and the placebo during a 4-week period per each agent with a washout period of at least 1 week between agents.	After 4 weeks of treatment with placebo, fluoxetine, sertraline and clomipramine the mean IELT was significantly increased from 46 s to 2.27 min, 2.30 min, 4.27 min and 5.75 min, respectively (all P < 0.01). However, treatment with clomipramine or sertraline caused a greater increase in mean IELT than fluoxetine or placebo (P < 0.01).
Akgul et al 2008 [56]	RCT	Sertraline 50 mg Citalopram 20 mg	8 weeks	80	Significant improvement was seen in both groups in terms of the IPE questionnaire results, from a mean (SD) pre-treatment score of 21.4 (1.8) to 39.8 (1.4) (P < 0.001) for citalopram group and from 20.9 (1.3) to 39.5 (2.9) (P < 0.001) for the sertraline group. However, the treatment response was not different between the two groups (P = 0.50).
Safarinejad and Hosseini, 2006 [55]	RCT	Citalopram 20 mg Placebo	12 weeks	58	The IELT after citalopram and placebo gradually increased from 32 and 28 s to ~268 and 38 s, respectively. The mean weekly intercourse episodes increased from pre-treatment values of 1.3 and 1.2 to 2.4 and 1.4, for citalopram and placebo, respectively (P < 0.05). Baseline mean intercourse satisfaction domain values of IIEF 10 and 11 reached to 16 and 10 at 12-week treatment in citalopram and placebo groups, respectively (P < 0.05).
Atmaca et al., 2002 [54]	RCT	Citalopram 20 mg ↑ to 60 mg Placebo	8 weeks	26	The increase in IELT in the citalopram group [week 0, mean (SD) 33.46 (17.9); week 8, 283.8 (80.5)] was statistically significant compared with the placebo group [week 0, 30.38 (14.6); week 8, 35.77 (13.5)] (P < 0.001).
Safarinejad, 2007 [65]	RCT	Escitalopram 10 mg Placebo	12 weeks	276	The escitalopram group had a 4.9-fold (95% CI 3.14–6.12) increase of the geometric mean IELT, whereas after placebo, the geometric mean IELT did not increase significantly (1.4-fold increase; 95% CI 0.86–1.68; P = 0.001).
Saleh et al., 2008 [66]	RCT	Escitalopram 10 mg Placebo	4 weeks	30	The mean (SD) score of IELT was significantly higher in escitalopram group as compared to placebo group after 30 days treatment, at 5.6 (0.7) vs 6.8 (0.4) (P < 0.03). At 90 days (2 months after stopping treatment), ILET score in the escitalopram group was significantly higher than the placebo group, at 6.7 (0.8) vs 3.4 (0.5) (P < 0.01).
Arafa and Shamloul, 2006 [71]	RCT	Sertraline 50 mg Placebo	4 weeks	147; crossover done after 1 week wash-out	Overall, 127 (81%) of 157 subjects had a significant increase in their AIPE total score after sertraline treatment. 66% of 100 patients available for follow-up had a relapse of PE within 6 months after sertraline withdrawal. IELT significantly improved in patients receiving sertraline vs placebo (P < 0.05)
Mathers et al., 2009 [153]	RCT	Sertraline 50 mg Vardenafil 20 mg	6 weeks	72; crossover done after 1 week wash-out	Initial mean (SD) PE scaled at 5.94 (1.6) and IELT was 0.59 min. Vardenafil improved PE grading: mean (SD) 2.7 (2.1) (P < 0.01) and IELT increased to 5.01 (3.69) min (P < 0.001). The mean (SD) PE grading improved 1.92 (1.32) (P < 0.01) and IELT 3.12 (1.89) min (P < 0.001) with sertraline.
Mendels et al., 1995 [154]	RCT	Sertraline 50 mg ↑ to 200 mg Placebo	8 weeks	52	Sertraline treatment produced significant improvements relative to placebo in time to ejaculation, at a mean (SD) of 1.16 (1.13) to 4.49 (2.9) vs 1.19 (1.38) to 2.46 (4.6) (P < 0.001); and number of successful attempts at intercourse, at a mean (SD) 0.58 (1.02) to 2.32 (2.4) vs 0.3 (0.47) to 0.75 (0.97) (P = 0.015), as well as overall clinical judgements of improvement.
Basar et al., 1999 [155]	RCT	Fluoxetine 20 mg for 1 week followed by 40 mg Sertraline 50 mg	4 weeks	57	In the fluoxetine group, 8 (30.8%) patients cured, improvement in 11 (42.3%) and failure in 7 (26.9%). In the sertraline group, 12 (38.7%) patients cured, improvement in 10 (32.3%) and failure in 9 (29%).
Xu et al., 2014 [72]	RCT	Sertraline 50 mg daily Mycelium of cordyceps sinensis C4	8 weeks	218; 63 patients chose to take sertraline 100 mg daily for an additional 4-week period, and 80 patients continued treatment with sertraline 50 mg.	Mean IELT of patients who subsequently chose to take 100 mg of sertraline was significantly lower than that of patients who continued taking 50 mg of sertraline, although the IELT value was comparable between the two groups of patients at baseline. However, with an additional 4-week treatment, the mean IELT increased significantly more in the 100-mg group than in the 50-mg continuation group.
McMahon, 1998 [31]	RCT	Sertraline 50 mg Placebo	4 weeks	37	The mean (range) pre-treatment IELT was 0.3 (0–1) min. The mean ejaculatory interval after 4 weeks of treatment was 3.2 min (range 1 min to anejaculation) with sertraline and 0.5 (0–1) min with placebo (P < 0.001).
Balbay et al., 1998 [156]	POS	Sertraline 50 mg	2 weeks	16	14 (87.5%) responded clinically. Clinical response was achieved in the first week of treatment in 11 of 16 responders (68.75%).
Abu El-Hamd and Abdelhameed, 2018 [88]	RCT	Paroxetine 30 mg Dapoxetine 30 mg Sildenafil 50 mg Placebo	6 weeks	150, 5 groups: placebo, paroxetine, dapoxetine, sildenafil and combined dapoxetine + sildenafil	The mean of IELT, satisfaction score and PEDT in all groups was significantly improved after treatment (P = 0.001). Combined dapoxetine with sildenafil group had the best values of IELT, satisfaction scores and PEDT in comparison with other treatment groups (P < 0.001).
Simsek et al., 2014 [89]	RCT	Dapoxetine (30 and 60 mg) Paroxetine (20 mg)	4 weeks	150, Group 1 were treated with on-demand dapoxetine (30 mg), Group 2 with on-demand dapoxetine (60 mg), and Group 3 with daily paroxetine (20 mg).	The IELT increased from baseline to post-treatment by 117%, 117% and 170% in the paroxetine group (P < 0.01), 30 mg dapoxetine group (P < 0.01) and 60 mg dapoxetine group (P < 0.01), respectively. The increase from baseline IELT were similar for the 30-mg dapoxetine and paroxetine groups (P > 0.05), while the 60-mg dapoxetine group had a larger post-treatment IELT increase compared with the 30-mg dapoxetine (P < 0.05) and paroxetine (P < 0.01) groups.
Waldinger et al., 1997 [75]	RCT	Paroxetine 20 mg Paroxetine 40 mg	7 weeks	27	Both groups showed a statistically significant difference from the baseline values of ejaculation latency (P < 0.001) and a clinically relevant improvement in ejaculation time. The increase in the IELT was not statistically significant different between the groups.
Alghobary et al., 2010 [78]	RCT	Paroxetine 20 mg Tramadol HCL 50 mg	12 weeks	35	After 12 weeks, a decline of IELT to fivefold was recorded with tramadol whereas further increase of IELT to 22-fold was recorded with paroxetine compared with baseline (P < 0.05). Tramadol improved AIPE score significantly after 6 weeks but not after 12 weeks vs baseline, whereas paroxetine increased the AIPE score after 6 and 12 weeks vs baseline (P < 0.05).
McMahon and Touma, 1999 [76]	PCS	Paroxetine 20 mg	4 weeks	94; Group A, once daily followed by on demand (n = 64) Group B, on demand (n = 33)	The mean (range) pre-treatment IELT of both Group A and B was 0.4 (0–1) min. In Group A, the mean ELT was 4.5 min (range 1–anejac.). 53/61 men in Group A regarded their ejaculatory control as improved and were then treated with ‘on-demand’ paroxetine, achieving an ELT of 3.9 min (range 0–10). 63 men in this group of 53 regarded that they had maintained improved ejaculatory control with a mean ELT of 5.5 min (range 2–20 min) after a further four weeks of treatment (P < 0.001). The remaining 17 men reported a recurrence of poor ejaculatory control with a mean ELT of 0.7 min (range 0–2 min). In group B with initial ‘on-demand’ paroxetine after a mean of 4.5 weeks of treatment, the mean ELT was 1.5 min (range 0–5 min).
Safarinejad, 2006 [77]	RCT	Dapoxetine 60 mg (Group 1, n = 115) Paroxetine 20 mg (Group 2, n = 113) Placebo (Group 3, n = 112)	12 weeks	340	At the end of the 12-week treatment with dapoxetine, paroxetine, and placebo, the mean IELT was increased from 38, 31 and 34 s to 179, 370 and 55 s, respectively (P = 0.01 in Group 1 and P = 0.001 in Group 2).
Salonia et al., 2002 [115]	RCT	Paroxetine 10–20 mg Sildenafil 50 mg	6 months	80; Group 1 – Paroxetine 10 mg daily then 20 mg on demand. Group 2 – Paroxetine 10 mg daily then 20 mg on demand + sildenafil 50 mg on demand	Mean (SE) IELT in Group 1 was 0.33 (0.04), 3.7 (0.10) (P < 0.01) and 4.2 (0.03) min (P < 0.01) at baseline, 3 and 6-month follow-up, while in Group 2 it was 0.35 (0.03), 4.5 (0.07) (P < 0.01) and 5.3 (0.02) min (P < 0.001), respectively. When improvement in IELT was compared in the two groups, Group 2 results proved to be significantly greater (P < 0.05).
Polat et al., 2014 [157]	RCT	Paroxetine 20 mg Tadalafil 20 mg	4 weeks	150; Group 1 – paroxetine daily for 1 month, Group 2 – tadalafil on demand, and Group 3 – paroxetine and tadalafil on demand	Statistically significant changes in IELT were detected in comparison to baseline results [mean (SD) Group 1: 60.6(30.2) to 117.3 (67.3) s, Group2: 68.5 (21.4) to 110.2 (37.3) s, Group 3: 71.56 (40.23) to 175.2 (60.2) s (P < 0.01). IELT scores after discontinuation of treatment were found to be close to the baseline IELT scores (P > 0.05).
Waldinger et al., 1998 [80]	RCT	Fluoxetine 20 mg Fluvoxamine 100 mg Paroxetine 20 mg Sertraline 50 mg Placebo	6 weeks	51	During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at ~20 s. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (P < 0.001); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to ~110 s, whereas in the fluvoxamine group, IELT was increased to only ~40 s. The paroxetine, fluoxetine, and sertraline groups differed significantly (P < 0.001, P < 0.001, P = 0.017, respectively) from placebo but the fluvoxamine group did not (P = 0.38).
Pryor et al., 2006 [86]	RCT	Dapoxetine 30 mg Dapoxetine 60 mg Placebo	12 weeks	1958	Dapoxetine significantly prolonged IELT (P < 0.001, all doses vs placebo). Mean (SD) IELT at baseline was 0.90 (0.47), 0.92 (0.50), and 0.91 (0.48) min, and at study endpoint (week 12 or final visit) was 1.75 (2.21) min for placebo, 2.78 (3.48) min for 30 mg dapoxetine, and 3.32 (3.68) min for 60 mg dapoxetine.
Kaufman et al., 2009 [84]	RCT	Dapoxetine 60 mg Placebo	9 weeks	1238	Personal distress related to ejaculation decreased from a mean (SD) of 2.8 (0.81) to 1.5 (1.05) in treatment group vs 2.8 (0.82) to 2 (1.05) in the placebo group. Perceived control over ejaculation improved from a mean (SD) of 0.6 (0.61) to 2.1 (1.13) in the treatment group vs 0.6 (0.59) to 1.6 (1.02) in the placebo group. Satisfaction with sexual intercourse improved from a mean (SD) of 1.4 (0.83) to 2.5 (1.11) in the treatment group vs 1.5 (0.79) to 2(1.01) in the placebo group.
Buvat et al., 2009 [83]	RCT	Dapoxetine 30 mg Dapoxetine 60 mg Placebo	24 weeks	618	Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9, 3.2, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1, 1.8, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine vs placebo at week 12 and week 24 (all P < 0.001).
McMahon et al., 2010 [85]	RCT	Dapoxetine 30 mg Dapoxetine 60 mg Placebo	12 weeks	858	Mean Average IELT increased from ~1.1 min at baseline (across groups) to 2.4, 3.9, and 4.2 min with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively; and geometric mean IELT increased from ~0.9 min at baseline (across groups) to 1.8, 2.7, and 3.1 min, respectively (fold-increases of 2.0, 2.8, and 3.3, respectively). All PEP measures and the CGI of change were significantly improved with dapoxetine vs placebo at study endpoint (P < or = 0.005 for all).
McMahon et al., 2013 [158]	RCT	Dapoxetine 30 mg Dapoxetine 60 mg Placebo	12 weeks	429	Arithmetic mean average IELT significantly increased with dapoxetine vs placebo at end point (5.2 vs 3.4 min) and weeks 4, 8, and 12 (P ≤ 0.002 for all). Men who described their PE at least ‘better’ using the CGI were significantly greater with dapoxetine vs placebo at end point (56.5% vs 35.4%) and weeks 4, 8, and 12 (all P ≤ 0.001). Significantly better outcomes were also reported with dapoxetine vs placebo on PEP measures.
Tuken et al., 2019 [159]	POS	Dapoxetine/Sildenafil combination 30/50 mg	4 weeks	53	The geometric mean (SD) IELT of the patients significantly increased from 22.72 (15.16) to 68.25 (82.33) s (P < 0.001). Similarly, significant improvements were observed in the mean (SD) PEP index score [0.86 (0.72) vs 2.36 (1.13); P < 0.001) and IIEF-EF domain score [13.17 (3.33) vs 24.60 (3.96); P < 0.001). According to the GIC results, 81.13% of the patients were satisfied with the treatment.
Peng et al., 2020 [160]	POS	Dapoxetine 30 mg	4 weeks	154	An obvious improvement compared with the baseline was found regarding mean (SD) IELT [2.4 (1.6) vs1.0 (0.7) min; P < 0.001) and mean NITBE [85.9 (61.9) vs 37.4 (28.6) times; P < 0.001). The proportion of patients with a self-evaluation of at least ‘slightly better’ and were categorised into ‘CGIC ≥1ʹ group was 70.1%.

CGI: Clinical Global Impression-Improvement scale; NITBE: number of intravaginal thrusts before ejaculation; POS: prospective observational study.

Table 4. List of the dosage, pharmacokinetics and side-effects of commonly prescribed TCAs and SSRIs for PE

Drug	Dosage, mg	Metabolism	Half life	Side-effects
Clomipramine [,79]	25	CYP2C19, CYP3A4, CYP1A2	10–70 h	Manic episode in both bipolar and unipolar disorders. Anticholinergic side-effects: dry mouth, blurring of vision, constipation, urinary retention and aggravation of narrow-angle glaucoma. Cardiac side-effects including tachycardia, flattened T waves, prolonged QT intervals, and depressed ST segments
Fluoxetine [161,162]	20–40 daily	CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4	1–4 days	Dizziness, dry mouth, nausea, constipation, weight gain, insomnia, tremors, prolonged QT interval, light headedness, confusion, agitation, sexual dysfunction
Citalopram [163,164]	20	CYP2C19, CYP2D6, CYP3A4	35 h
Escitalopram [165–168]	10	CYP2C19, CYP3A4	35 h
Sertraline [79]	25–50	CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4	26 h
Paroxetine [73,74,169]	20	CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4	Variable depends on dose
Fluvoxamine [79,170]	50–300	CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4	15 h and 17 to 22 h
Dapoxetine [82,171]	30 or 60	CYP2D6, CYP3A4	1.4 and 20 h

Figure 2. Mechanism of action of SSRIs at the synaptic terminal

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