Introduction

The efficacy of most antipsychotic drugs is considered to be mediated by dopamine transmission attenuation through their actions as antagonists or low-efficacy partial agonists at the dopamine D2 receptor (D2R). However, antipsychotics have the risks of adverse events such as hyperprolactinemia-related sexual dysfunction. Prolactin production is inhibited in the hypothalamo–pituitary circuit through dopamine release and can be disinhibited by blocking D2R. Hyperprolactinemia causes several sexual dysfunctions. Sexual dysfunctions have been one of the most frequently reported motives for treatment discontinuation in schizophrenia and have been associated with impaired quality of life in individuals with schizophrenia.1,2 Recent systematic reviews identified erectile dysfunction (ED) as the most prevalent sexual dysfunction for men with schizophrenia.3,4 Clinical practice guidelines recommend that individuals with sexual dysfunction consider switching from prolactin-elevating antipsychotics to prolactin-sparing antipsychotics (Table 1).5–11 However, several individuals with schizophrenia responded to only prolactin-increasing antipsychotics. Hence, the development of novel treatments underscoring improving sexual dysfunctions is a pressing issue in schizophrenia research. Phosphodiesterase-5 inhibitors (PDE5-Is) are generally recommended for ED in the general population.12,13 PDE5-Is work by increasing levels of cyclic GMP (cGMP) in smooth muscle cells, leading to vasodilation. Specifically, they inhibit the enzyme PDE5, which normally breaks down cGMP. By preventing this breakdown, PDE5 inhibitors allow cGMP to accumulate, causing smooth muscle relaxation and vasodilation. In the context of ED, this vasodilation occurs in the corpus cavernosum of the penis, facilitating increased blood flow and an erection.14 Commonly reported adverse effects associated with PDE5-Is therapy include headache, facial flushing, dyspepsia, disturbances in color vision, hypotension, dizziness, and nasal congestion.14 This systematic review and meta-analysis aimed to identify the PDE5-I that is better for sexual dysfunction treatment in individuals with schizophrenia.

Table 1 Treatment Recommendation for Treatment of Erectile Dysfunction in the Clinical Practical Guidelines

Methods

This systematic review was conducted under the PRISMA statement (Table S1)15 and was registered at the Open Science Framework (https://osf.io/2jdn5).

Search Strategy, Inclusion Criteria, and Data Extraction

This systematic review included only double-blind, randomized, placebo controlled trials (DBRPCTs). Figure S1 summarizes the formal literature search and selection flow of PDE5-Is trials. A formal systematic literature review was conducted using the Patient, Intervention, Comparison, and Outcome strategy. Participants included individuals with schizophrenia spectrum and other psychotic disorders who received antipsychotics. The intervention involves avanafil, icariin, lodenafil, osajin, sildenafil, tadalafil, udenafil, vardenafil, yonkenafil, and zaprinast which were introduced as a PDE5-Is in our previous review.16 We conducted a comparison with placebo, and outcomes are presented as follows. At least two authors simultaneously and independently performed the literature search and data extraction, the obtained data were input into a spreadsheet for analysis, and assessed all data for accuracy. We included all DBRPCTs that matched the aforementioned PICO criteria. A DBRPCT including both male and female participants was also included. An open-label study was excluded.

Outcome Measures and Data Synthesis

Our primary outcome includes ED assessed using standardized questionnaires. Other efficacy outcomes involve overall sexual dysfunction, overall schizophrenia symptoms (Positive and Negative Syndrome Scale (PANSS)17 and Brief Psychiatric Rating Scale (BPRS),18 positive symptoms (PANSS and BPRS), and negative symptoms (PANSS and BPRS). Further, we included all-cause discontinuation, discontinuation due to adverse events, discontinuation due to consent withdrawal, headache, loss of appetite, and somnolence.

Our meta-analysis primarily utilized data based on the intention-to-treat or full analysis set principles. We did not obtain any unpublished data.

Meta-Analysis Methods

A random-effects pairwise meta-analysis was conducted according to the aforementioned outcomes to compare a specific drug with a placebo.19 Effect sizes were risk ratios for dichotomous outcomes and standardized mean differences for continuous outcomes. The heterogeneity of the included trials was assessed using the I2 statistic.20 The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials version 2.20 We did not evaluate a publication bias because only three studies were conducted on sildenafil.20 Comprehensive Meta-Analysis version 4 (Biostat Inc., Englewood, NJ, USA) was used for statistical analysis of our meta-analysis.

Results Literature Search

The result of literature search was shown in Figure S1. Our systematic review and meta-analysis included five trials that involved a total of 155 individuals (Figure S1).21–25Table 2 shows the study characteristics. Concerning the overall risk of bias, four studies were assessed as some concern and one study as low risk (Table S2).

Table 2 Study Characteristics

Figure 1 Continued.

Figure 1 Forest plots.

Abbreviations: 95% CI, 95% confidence interval; MH, Mantel-Haenszel; Std diff in means, standardized difference in means.

Systematic Review Lodenafil Nunes Study (Brazil)

This was a 16-week, double-blind, randomized, crossover, placebo-controlled trial with lodenafil that included male patients with stable psychotic symptoms of schizophrenia and schizoaffective disorder comorbid ED (n = 50, mean age ± standard deviation [SD] = 37.26 ± 8.89 years). Lodenafil did not outperform the placebo in terms of the Arizona Sexual Experiences Scale (ASEX)26 total score, ASEX penile erection subscale score, International Index of Erectile Function (IIEF)27 total score, IIEF erectile function subscale score, and PANSS total score.

Sildenafil Akhondzadeh Study (Iran)

This was an 8-week, double-blind, randomized, placebo controlled trials with sildenafil that included male (90.00%) and female patients with schizophrenia with acute exacerbation (n = 40, mean age ± SD = 33.36 ± 8.27 years). Sildenafil outperformed placebo in terms of PANSS total, negative subscale, and general subscale scores but not PANSS positive subscale scores. This study did not assess sexual dysfunction-related outcomes.

Goff Study (USA)

This was a 2-day, double-blind, randomized, crossover, placebo-controlled trial with sildenafil that included male (47.06%) and female patients with stable psychotic symptoms of schizophrenia (n = 17, mean age ± SD = 49.7 ± 0.6 years). Sildenafil did not outperform placebo in terms of BPRS total score and positive, negative, and depression subscale scores. This study did not assess sexual dysfunction-related outcomes.

Gopalakrishnan Study (India)

This was a 4-week, double-blind, randomized, crossover, placebo-controlled trial with sildenafil that included male patients with stable psychotic symptoms of schizophrenia and delusional disorder comorbid ED (n = 32, mean age ± SD = 35.1 ± 5.5 years). Sildenafil outperformed placebo in terms of the number of adequate erections, sexual intercourse satisfaction, and erection duration when assessed using the Global Efficacy Questionnaire.28 This study did not assess for psychopathology-related outcomes.

Tadalafil de Boer Study (Netherlands)

This was a 6-week, double-blind, randomized, crossover, placebo-controlled trial with tadalafil that included male patients with schizophrenia and schizoaffective disorder comorbid ED (n = 16, mean age ± SD = 37.4 ± 6.6 years). Tadalafil outperformed placebo in terms of Improvement Global Usefulness and Antipsychotics and Sexual Functioning Questionnaire29,30 total score but not IIEF total score, IIEF erectile function subscale score, PANSS total score, and PANSS positive, negative, and general subscale scores.

Meta-Analysis Including Sildenafil Studies

Only sildenafil, which had three trials, was assessed for its characteristics using a meta-analysis. However, our meta-analysis did not include efficacy outcomes for sexual dysfunction due to insufficient data. No significant differences in other outcomes were found between sildenafil and placebo (Figure 1 and Table 3).

Table 3 Results of Meta-Analysis Including Sildenafil Studies

Discussion

Among the three studies on sildenafil, only one reported outcomes on sexual dysfunction; however, it demonstrated that sildenafil improved ED in males with schizophrenia. In addition, the sole study on tadalafil also found that tadalafil was effective in improving ED in males with schizophrenia. Taken together, our systematic review suggested that sildenafil and tadalafil might represent potential treatment options for ED in males with schizophrenia. Furthermore, the results of our meta-analysis indicated that sildenafil was generally well-accepted and well-tolerated. However, these findings were based on only two studies, highlighting the need for further research.

One study of sildenafil for schizophrenia with acute exacerbation reported that sildenafil improved psychopathology, especially negative symptoms; however, other sildenafil studies for stable schizophrenia did not demonstrate such findings. Further, tadalafil did not improve psychopathology for stable schizophrenia. Thus, the discrepancy in efficacy results for psychopathology may be explained by the difference in the patient’s condition (ie, acute phase or maintenance phase). However, at least PDE5-Is are unlikely to make psychopathology in individuals with schizophrenia worse.

Individuals with schizophrenia have a higher risk of coronary artery disease.31 The drug insert package states that “patients should not use sildenafil and tadalafil if sexual activity is inadvisable due to cardiovascular status.”32 Therefore, clinicians should carefully check the heart conditions of patients before providing these PDE5-Is.

A recent meta-analysis reported that adding aripiprazole to existing treatment significantly decreased prolactin levels.33 However, aripiprazole has a risk of akathisia and somnolence although the effect sizes were low when compared with placebo.34,35

Our study had several limitations. First, only one study revealed the positive results. Second, the study duration of each trial was short. A longer-duration study involving a larger sample is warranted as individuals with schizophrenia have a long-term treatment period. Third, the scales for sexual dysfunction used in each study were not consistent. The characteristics of each scale may have affected sexual dysfunction-related outcomes (eg, questions that are affected by whether or not a patient has a partner). Finally, we did not assess whether PDE5-Is had a benefit for sexual dysfunction treatment in women with schizophrenia.

In conclusion, our systematic review suggested that sildenafil and tadalafil might represent potential treatment options for ED in males with schizophrenia. Furthermore, the results of our meta-analysis indicated that sildenafil was generally well-accepted and well-tolerated. However, these findings were based on only two studies, highlighting the need for further research. Clinicians should address the cause of ED, such as antipsychotic-induced hyperprolactinemia, if possible.

Data Sharing Statement

Data used for the current study were reported in articles as cited in this paper.

Ethical Approval

The requirement for ethical approval was waived in this study because it did not involve any human subjects, and the data retrieved for synthesis was collected from published studies.

Acknowledgments

Mr. Akiyoshi Saito participated in the project as a Student Assistant funded by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan’s Project for Forming Centers for Advanced Medical Human Resource Development. We would like to thank MARUZEN-YUSHODO Co., Ltd. (https://kw.maruzen.co.jp/kousei-honyaku/) for the English language editing.

Funding

We acknowledge funding provided by JSPS KAKENHI (19K08082). The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclosure

Dr. Sakuma has received speaker’s honoraria from Janssen, Kyowa, Meiji, Otsuka, Sumitomo, and Takeda and has received Grant-in-Aid for Young Scientists (B)(19K17099) and Japan Agency for Medical Research and Development (JP22dk0307107). Prof. Iwata received speaker’s honoraria from Sumitomo, Eisai, Janssen, Otsuka, Meiji, Shionogi, Takeda, Yoshitomiyakuhin, and Viatris and research grants from Eisai, Takeda, Sumitomo, and Otsuka. Prof. Kishi has received speaker’s honoraria from Eisai, Janssen, Meiji, Otsuka, Sumitomo, Takeda, Mitsubishi-Tanabe, Kyowa, Boehringer Ingelheim, and Viatris and research grants from Eisai, JSPS KAKENHI (19K08082, 23K06998, and 25K10874), Japan Agency for Medical Research and Development (JP22dk0307107, JP22wm0525024, 23dk0307117h0001, and 24dk0307129h0001), and the Japanese Ministry of Health, Labour and Welfare (21GC1018). The authors report no other conflicts of interest in this work.

References

1. Bebbington PE, Angermeyer M, Azorin JM, Marwaha S, Marteau F, Toumi M. Side-effects of antipsychotic medication and health-related quality of life in schizophrenia. Acta Psychiatr Scand Suppl. 2009;(438):22–28. doi:10.1111/j.1600-0447.2008.01310.x

2. Lambert M, Conus P, Eide P, et al. Impact of present and past antipsychotic side effects on attitude toward typical antipsychotic treatment and adherence. Eur Psychiatry. 2004;19(7):415–422. doi:10.1016/j.eurpsy.2004.06.031

3. Dumontaud M, Korchia T, Khouani J, et al. Sexual dysfunctions in schizophrenia: beyond antipsychotics. A systematic review. Prog Neuropsychopharmacol Biol Psychiatry. 2020;98:109804. doi:10.1016/j.pnpbp.2019.109804

4. Korchia T, Achour V, Faugere M, et al. Sexual dysfunction in schizophrenia: a systematic review and meta-analysis. JAMA Psychiatry. 2023;80(11):1110–1120. doi:10.1001/jamapsychiatry.2023.2696

5. Barnes TR, Drake R, Paton C, et al. Evidence-based guidelines for the pharmacological treatment of schizophrenia: updated recommendations from the British association for psychopharmacology. J Psychopharmacol. 2020;34(1):3–78. doi:10.1177/0269881119889296

6. Remington G, Addington D, Honer W, Ismail Z, Raedler T, Teehan M. Guidelines for the pharmacotherapy of schizophrenia in adults. Can J Psychiatry. 2017;62(9):604–616. doi:10.1177/0706743717720448

7. NICE. 2014. Psychosis and Schizophrenia in Adults: Prevention and Management. National Institute for Health and Care Excellence: Guidelines National Institute for Health and Care Excellence.

8. Galletly C, Castle D, Dark F, et al. Royal Australian and New Zealand college of psychiatrists clinical practice guidelines for the management of schizophrenia and related disorders. Aust N Z J Psychiatry. 2016;50(5):410–472. doi:10.1177/0004867416641195

9. Hasan A, Falkai P, Wobrock T, et al. World federation of societies of biological psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry. 2013;14(1):2–44. doi:10.3109/15622975.2012.739708

10. JSNP. Japanese society of neuropsychopharmacology: “guideline for pharmacological therapy of schizophrenia”. Neuropsychopharmacol Rep. 2021;41(3):266–324. doi:10.1002/npr2.12193

11. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American psychiatric association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868–872. doi:10.1176/appi.ajp.2020.177901

12. Burnett AL, Nehra A, Breau RH, et al. Erectile dysfunction: AUA guideline. J Urol. 2018;200(3):633–641. doi:10.1016/j.juro.2018.05.004

13. Domes T, Najafabadi BT, Roberts M, et al. Canadian urological association guideline: erectile dysfunction. Can Urol Assoc J. 2021;15(10):310–322. doi:10.5489/cuaj.7572

14. Dhaliwal A, Gupta M. PDE5 inhibitors. StatPearls. 2025.

15. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021:372:n71. doi:10.1136/bmj.n71

16. Sakuma K, Kishi T, Sanji S, et al. Phosphodiesterase type 5 inhibitors for the treatment of sexual dysfunction in males with major depressive disorder: a systematic review and meta-analysis. Psychiatry Clin Neurosci. 2023;77(5):297–299. doi:10.1111/pcn.13537

17. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. doi:10.1093/schbul/13.2.261

18. Overall J, Gorham D. Brief psychiatric rating scale. Psychol Rep. 1962;10(3):799–812. doi:10.2466/pr0.1962.10.3.799

19. DerSimonian R, Laird N. Meta-analysis in clinical trials. research support, U.S. Gov’t, P.H.S. Controlled Clin Trials. 1986;7(3):177–188. doi:10.1016/0197-2456(86)90046-2

20. Higgins J, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions version 6.3 (updated February 2022). 2022. Available from: www.trainingcochrane.org/Handbook. Accessed August27, 2025.

21. Akhondzadeh S, Ghayyoumi R, Rezaei F, et al. Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial. Psychopharmacology. 2011;213(4):809–815. doi:10.1007/s00213-010-2044-z

22. de Boer MK, Oolders JM, van den Heuvel ER, Wiersma D, Schoevers RA, Knegtering H. Efficacy of tadalafil on erectile dysfunction in male patients using antipsychotics: a double-blind, placebo-controlled, crossover pilot study. J Clin Psychopharmacol. 2014;34(3):380–382. doi:10.1097/JCP.0000000000000113

23. Goff DC, Cather C, Freudenreich O, et al. A placebo-controlled study of sildenafil effects on cognition in schizophrenia. Psychopharmacology. 2009;202(1–3):411–417. doi:10.1007/s00213-008-1278-5

24. Gopalakrishnan R, Jacob KS, Kuruvilla A, Vasantharaj B, John JK. Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry. 2006;163(3):494–499. doi:10.1176/appi.ajp.163.3.494

25. Nunes LV, Lacaz FS, Bressan RA, Nunes SO, Mari Jde J. Adjunctive treatment with lodenafil carbonate for erectile dysfunction in outpatients with schizophrenia and spectrum: a randomized, double-blind, crossover, placebo-controlled trial. J Sex Med. 2013;10(4):1136–1145. doi:10.1111/jsm.12040

26. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The arizona sexual experience scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26(1):25–40. doi:10.1080/009262300278623

27. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49(6):822–830. doi:10.1016/s0090-4295(97)00238-0

28. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil study group. N Engl J Med. 1998;338(20):1397–1404. doi:10.1056/NEJM199805143382001

29. Knegtering H, van den Bosch R, Castelein S, Bruggeman R, Sytema S, van Os J. Are sexual side effects of prolactin-raising antipsychotics reducible to serum prolactin? Psychoneuroendocrinology. 2008;33(6):711–717. doi:10.1016/j.psyneuen.2008.02.008

30. Knegtering H. Antipsychotic treatment and sexual functioning: Role of prolactin [PhD Thesis]. University of Groningen, University Medical Center Groningen The Netherlands; 2003; http://dissertations.ub.rug.nl/faculties/.

31. Correll CU, Solmi M, Veronese N, et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatry. 2017;16(2):163–180. doi:10.1002/wps.20420

32. FDA. U.S. food and drug administration. Available from: https://wwwfdagov/. Accessed August27, 2025.

33. Lu Z, Sun Y, Zhang Y, et al. Pharmacological treatment strategies for antipsychotic-induced hyperprolactinemia: a systematic review and network meta-analysis. Transl Psychiatry. 2022;12(1):267. doi:10.1038/s41398-022-02027-4

34. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951. doi:10.1016/S0140-6736(19)31135-3

35. Kishi T, Ikuta T, Sakuma K, Okuya M, Iwata N. Efficacy and safety of antipsychotic treatments for schizophrenia: a systematic review and network meta-analysis of randomized trials in Japan. J Psychiatr Res. 2021;138:444–452. doi:10.1016/j.jpsychires.2021.04.032