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The following information was provided to us by Dr. Melcangi and his team:

1. Identification of possible genes altered in the hypothalamus (i.e., the brain region more important for neuroendocrine control). To do that, we are using mRNA sequencing analysis (i.e., an innovative analysis that uses next-generation sequencing to reveal the presence and quantity of differentially expressed mRNA in a biological sample) in male rats treated with paroxetine. The effect of this SSRI will be explored after subchronic treatment and during withdrawal. We are conducting the same analysis in animals treated with finasteride, so it will be interesting to verify whether common genes are affected in PSSD and PFS.
2. Morphology of peripheral nerves, myelination process, and intraepidermal nerve fiber density (Small Fiber Neuropathy). Indeed, PSSD patients report genital numbness or paresthesia, suggesting peripheral neuropathy. In this context, it is important to highlight that we have demonstrated that PFS patients show peripheral neuropathy (Melcangi R.C. et al., J Steroid Biochem Mol Biol 2017).
3. Many clinical endpoints and reliable biomarkers are missing when considering PSSD. Hence, we aim to investigate the potential role of MicroRNAs in the PSSD experimental model as a biomarker for PSSD. MicroRNAs are a class of small, non-coding RNAs that regulate gene expression. These molecules possess the necessary characteristics to be considered ideal biomarkers, including accessibility, high specificity, and sensitivity. MicroRNAs are already utilized as biomarkers in various cancer types, cardiovascular diseases, sepsis, and nervous system disorders. Therefore, evaluating their role in the PSSD experimental model will provide a proof of concept for expanding their exploration in clinical settings.
4. In our ongoing exploration to understand the potential common pathways between Post-Finasteride Syndrome (PFS) and PSSD, we made an important discovery. Our recent data (Giatti S. et al., J. Mol. Struct., 2022) confirms that paroxetine, similar to finasteride, has the ability to inhibit phenylethanolamine N-methyltransferase (PNMT), the key enzyme involved in the production of the stress hormone epinephrine. This finding builds upon our previous observations (Giatti S. et al., J. Med. Chem. 2021) in a post-finasteride experimental model, which demonstrated finasteride's interaction with off-target proteins. The significance of this discovery lies in the suggestion that the research conducted on PFS may offer valuable insights into PSSD and vice versa. We believe this is a crucial development as it indicates a potential overlap in pathways between these two conditions. In light of these findings, we are now investigating whether paroxetine's interaction with PNMT is unique to this particular medication or if other SSRIs possess similar capabilities.
5. We aim to investigate the potential brain pathways leading to sexual dysfunction. In rodent experimental models, we will assess male sexual motivation and performance through behavioral tests. The information obtained from these tests will also indicate the key brain areas involved, allowing us to focus our subsequent molecular analysis on these tissues.
6. The gut-brain axis is widely recognized for its significance, as the gut communicates with the brain through the vagus nerves and gut microbiota. However, it is still unclear whether microbial molecular mediators, negatively affected by paroxetine treatment, play a role. Therefore, we will evaluate bacteria-derived metabolites such as short-chain fatty acids, serotonin, dopamine, and other neurotransmitters to explore their involvement in the effects of paroxetine on the brain.
7. Our observations have been obtained so far only in males; however, PSSD also occurs in females. Considering that neurosteroidogenesis and gut microbiota population, which are affected by paroxetine treatment in males, have been demonstrated to be influenced in a sex-dimorphic manner by various neuropathologies, it is possible that these two parameters may also be affected differently by paroxetine treatment in females. Therefore, we intend to explore the effect of paroxetine on neurosteroidogenesis and gut microbiota in females. Additionally, in this experimental model, it would be interesting and useful to investigate the potential involvement of the female vaginal microbiome in the context of sexual impairment and estrus cycle alterations.

In addition to supporting Dr. Melcangi's research, we are actively looking for other research opportunities with the guidance of our scientific advisor, Dr. Antonei Csoka.

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Dr. Melcangi and his team are continuously working on the issue of PSSD. There is no specific timeframe for when they will start or stop conducting research.

They have informed us that they urgently require funds in order to accelerate their research and conduct more testing. With additional funding, they believe they can make significant progress.

Despite receiving only around 50,000 EUR over the past few years, Dr. Melcangi and his team have managed to publish several papers within a short span of time.

Dr. Melcangi's ability to conduct his desired research at an estimated cost of approximately 80,000 EUR annually is made feasible through the support of the University of Milan. The university contributes to covering a portion of the research costs, allowing Dr. Melcangi to pursue his studies more efficiently.

Yes, we will stay in regular contact with Dr. Melcangi and ask him if he has any significant findings to share.

Currently, research is being conducted on male rats. Dr. Melcangi also intends to explore the effects of this condition on female rats and, eventually, on humans.

In the near future (the timing depends on funding), they plan to evaluate the role of microRNAs in their animal model and subsequently expand this investigation to a clinical setting.

Dr. Melcangi does not have one specific theory on PSSD and aims to approach this matter scientifically by examining the observed changes and drawing conclusions based on research results.

He believes that PSSD is a complex condition likely involving multiple systems, rather than a single specific issue.

Dr. Melcangi and his team aim to persuade other researchers to investigate PSSD, which can only be accomplished by documenting real changes.

Additionally, Dr. Melcangi's goal is to identify a biomarker for PSSD. One approach he intends to explore is the use of microRNAs, which have already been utilized as biomarkers in various diseases, such as cancer.

In short, Melcangi is focusing on the following:

• Identifying possible genes altered in the hypothalamus using mRNA sequencing analysis
• Investigating the potential role of microRNAs in the PSSD experimental model as a possible biomarker for PSSD
• Studying the morphology of peripheral nerves, the myelination process, and intraepidermal nerve fiber density (Small Fiber Neuropathy)
• Evaluating metabolites such as short-chain fatty acids, serotonin, dopamine, and other neurotransmitters to investigate their involvement in the effects of paroxetine on the brain
• Exploring potential brain pathways leading to sexual dysfunction
• Further investigating a common inhibited enzyme (PNMT) that is inhibited by both finasteride and paroxetine (based on previous findings)

Unfortunately, it is difficult to secure external funding for PSSD research due to the lack of interest from the medical community, absence of official recognition, and the absence of a definitive biomarker.

We are currently working towards obtaining grant funding, but in the meantime we intend to publish more research and generate interest in PSSD among the broader medical community.

Both methods have advantages and disadvantages. The biggest advantage of using rats is the cost and time efficiency in conducting studies.

A systematic review of 14 rat studies suggests that rats can develop persistent sexual dysfunction from taking SSRIs. This indicates that PSSD can occur in rats.

To provide some context regarding the time it takes for human studies to be completed and published, it is worth noting that the Baylor clinical study on PFS (Post-Finasteride Syndrome) took 7 years before it was published. Similarly, the recent PFS Kiel study is expected to take approximately 2-3 years before its findings are published.

Rat studies come with a wide range of advantages over human studies, such as the following:

Ethical Considerations

It helps avoid ethical concerns and is easier to obtain approval for compared to clinical studies. Additionally, it enables researchers to test different interventions or treatments before moving on to human trials. In the case of PSSD, studying rats allows researchers to for example directly examine the gene expression in the brain, which is not feasible with live humans.

Cost-Effectiveness

Rat studies are generally less expensive than human studies. Rats are readily available, easy to house and maintain, and have shorter lifespans, reducing overall costs.

Controlled Environment

Conducting studies on rats allows for a more controlled environment. Researchers can regulate factors such as diet, living conditions, and exposure to external influences, which can be challenging to control in human studies.

Genetic manipulation

Rats offer greater flexibility for genetic manipulation and controlled breeding, allowing researchers to study specific genetic factors and their impact on health, behavior, and diseases.

The following information was provided to us by Dr. Melcangi and his team:

1. Giatti S., Diviccaro S., Cioffi L., Melcangi R.C. Post-Finasteride Syndrome and Post-SSRI Sexual Dysfunction: Two clinical conditions apparently distant, but very close. Frontiers in Neuroendocrinology, 2023, 101114, ISSN 0091-3022, https://doi.org/10.1016/j.yfrne.2023.101114.
2. Diviccaro S., Giatti S., Cioffi L., Falvo E., Piazza R., Caruso D., Melcangi R.C. Paroxetine effects in adult male rat colon: Focus on steroidogenesis and microbiota. Psychoneuroendocrinology 143: 105828, 2022 https://doi.org/10.1016/j.psyneuen.2022.105828
3. Giatti S., Di Domizio A., Diviccaro S., Cioffi L., Marmorini I., Falvo E., Caruso D., Contini A., Melcangi R.C. Identification of a novel off-target of paroxetine: Possible role in sexual dysfunction induced by this SSRI antidepressant drug. J. Mol. Structure 1268:133690, 2022 https://doi.org/10.1016/j.molstruc.2022.133690
4. Healy D., Bahrick A., Bak M., Barbato A., Calabrò R.S., Chubak B.M., Cosci F., Csoka A.B., D'Avanzo B., Diviccaro S., Giatti S., Goldstein I., Graf H., Hellstrom W.J.G., Irwig M.S., Jannini E.A., Janssen P.K.C., Khera M., Kumar M.T., Le Noury J., Lew-Starowicz M., Linden D.E.J., Lüning C., Mangin D., Melcangi R.C., Rodríguez O.W.M.A.A.S., Panicker J.N., Patacchini A., Pearlman A.M., Pukall C.F., Raj S., Reisman Y., Rubin R.S., Schreiber R., Shipko S., Vašečková B., Waraich A. Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin. Int J Risk Saf Med. 33:65-76, 2022
5. Giatti S., Diviccaro S., Cioffi L., Falvo E., Caruso D., Melcangi R.C. Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis. Psychoneuroendocrinology 132:105364, 2021.
6. Giatti S., Diviccaro S., Panzica G., Melcangi R.C. Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin? Endocrine 61:180-193, 2018.