Inclusion of Women in French Psychiatric Clinical Trials: A Qualitative Study of Researchers’ Experiences and Challenges

Inclusion of Women in French Psychiatric Clinical Trials: A Qualitative Study of Researchers’ Experiences and Challenges | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Inclusion of Women in French Psychiatric Clinical Trials: A Qualitative Study of Researchers’ Experiences and Challenges François Berthet, Anne Le Jeannic, Franck Rolland This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6718965/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Since the thalidomide crisis, women have been underrepresented in clinical studies, leading to inequalities in knowledge and clinical consequences. International recommendations promoting women’s inclusion and gender consideration by the World Health Organization (WHO) and the Lancet Group highlight the recent increase in awareness. There is growing evidence that gender is a central factor in neurophysiological and psychiatric disorders in all aspects. In France, these specificities have been mainly unaddressed. Methods: We performed seven semistructured interviews with French psychiatrist researchers. Qualitative analysis was performed, and themes and subthemes were generated deductively on the basis of bibliography inductively via grounded theory. Semiquantitative analysis was performed via Iramuteq software. Results: In clinical practice, taking care of pregnant women is considered an anxious situation, as the safety of treatment is considered uncertain. The participants were favorable toward women inclusion without limitations. Clinical research associates are more burdened when dealing with the inclusion of women than with that of men. Relation with research ethics committees (RECs) is described as challenging, leading to the implementation of umbrella protocols and expecting refusals to include pregnant, breastfeeding and nonusing contraceptive women. Discussion: Underrepresentation of women in clinical trials in psychiatry has led to a gap in knowledge that cannot be filled by retrospective studies. Switching the paradigm from protection from research to protection through participation, as proposed by the WHO, could address this gap. We argue that biomedical research should move beyond the rigid application of the precautionary principle and adopt a precaution ethics approach, which acknowledges that lack of evidence can itself generate ethical risk. The fluctuation of anosognosia, which is specific to psychiatric diseases, may expose pregnant women to not seek help when they are experiencing a resurgence of symptoms. Criticisms made on French REC concur with international literature. Improving education in research ethics and facilitating communication between RECs and researchers may enhance the representation of women in psychiatric clinical trials. terms ethics research gender role psychiatry Figures Figure 1 Figure 2 Figure 3 Introduction For decades, women and, more generally, female sex has been underrepresented in biomedical research, leading to inequalities in knowledge (1). Following the Thalidomide crisis, the Food and Drug Administration (FDA) has excluded childbearing potential women from early dosing studies since 1977 (2). Consequently, women were not included until the phase 3 trial. However, during the HIV epidemic, evidence emerged that women react differently than men do: a longer incubation time, worse tolerance and greater efficiency of treatment (3) led to a new law, voted upon by the American Congress in 1993: the inclusion of women and minorities became mandatory to gain access to financial support from the National Institute of Health. On the other hand, preclinical studies also present inequalities in sex representation, leading to greater side effects for women, which could have been foreseen (4). For example, the dosage of the drug zolpidem has been adapted by sex 10 years after it was commercialized by the FDA due to increased reports of side effects in women secondary to a half-life in blood two times greater than those in men (5–7) . Furthermore, underrepresentation of female sex can lead to misdiagnosis and treatment of specific diseases, such as myocardial infarction, as their clinical presentation and pathophysiology differ from those of men (7,8). With respect to this underrepresentation, the World Health Organization (WHO) published guidelines for health-related research in humans in 2016 (9). Two chapters of these guidelines focus on women’s inclusion, in which the systematic exclusion of women after the Thalidomide crisis is considered problematic. While considering the potential vulnerability of women during clinical studies, it must be considered an extrinsic factor that is based mainly on society and lacks specific knowledge (10). In Europe, the editorial board of the Lancet has produced specific guidelines for authors to consider gender in studies (11). In psychiatry and neurophysiology, increasing evidence highlights the importance of gender considerations in research and clinical practice: women present more resistance to antidepressants, specific patterns of consumption when dealing with cocaine addiction, different ages of schizophrenia onset, and twofold greater risks of developing Alzheimer’s disease (12–15); furthermore, a recent publication revealed the potential role of estrogens as a treatment for psychiatric disease for women (16). In France, decades of effort in women’s cancer research have been made through the E3N cohort, enabling high-quality studies on women’s health (17,18). However, the specificities of women’s mental health in France have been mainly unaddressed by the Senatorial Commission of 2015 (19). In 2023, a report produced by French deputes on women’s mental health recommended equal inclusion of both genders in psychiatric biomedical studies, but it remains lightly justified (20). In this context of the global underrepresentation of women in biomedical research and the recent awareness in the French psychiatric field, we propose to answer the following question: According to French psychiatrists, what are the factors that promote or impede the inclusion of women in biomedical research? Methodology Study design and setting We performed exploratory qualitative research among French psychiatrists with active research activities. The study was designed by FB. FB realized the semiquantitative analysis, and FR overviewed it. FB drafted the manuscript, and FR and ALJ reviewed the manuscript providing substancial corrections. FB is a male psychiatrist with experience in quantitative research who is conducting his first qualitative research for a master’s degree. FR is a male psychiatrist with a master’s degree in the ethics field with experience in qualitative research. ALJ is a female psychiatrist. Semistructured interviews (SSIs) were conducted by FB. The initial interview guide was developed specifically for this study based on a review of the relevant literature and was adapted iteratively as themes emerged during the interviews. The final version of the guide is provided in the appendix. An email was sent to the participants describing the subject, field of research and professional status of FBs; in the absence of response, a second email was sent 15 days later. First, emails were sent by convenience, after which snowball sampling methodology was used: participants were asked two potential participants. At the end of the SSI, an informal conversation was initiated. This research was approved by an ethics committee. The manuscript has been drafted according to the 32 items of the COREQ checklist (20). Data collection SSI was conducted privately once at the workplace of the participant. Consent was audio-recorded at the beginning of the interview. One interview was 30 minutes long, the majority lasted one hour, and field notes were taken. Data were collected between February and May 2024. Data analysis Audio data were transcribed and received a random code with one letter and one number. A table was created with the code and participant characteristics, and then the transcriptions were deidentified before analysis. Themes were generated deductively from the literature and inductively on the basis of grounded theory (21). Analysis was performed with Taguette, an open source software (22), by FB. The quotation has been translated to English by FB. All the interviews were analyzed. The sociogram presented in the results section was created according to Moreno theory (23). A lexicometric analysis was performed with Iramuteq (24) after the qualitative analysis ended. Deidentified transcriptions were united in one file, with the exclusion of informal discussions, and individual interviews were used as variables for analysis. We used the default parameters proposed by the software. Results Thirty-nine potential participants were contacted, most of whom did not respond after the second email. Ten agreed to participate, but three canceled their participation. The participants’ ages ranged between 29 and 50 years, with 3 males and 4 womens. The field of studies conducted by participants was large (schizophrenia, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and addiction), with a variety of methodologies (fMRI, psychotherapy and transcranial stimulation). Three participants reported conducting studies in foreign countries. One participant knew the interviewer, as they had worked together for half a year. The results of the qualitative analysis are presented in Fig. 1 . The “Ethics committee” theme emerged from grounded theory: it has deductively emerged from the first interview and was confirmed by the second. Data saturation was reached after the fourth interview, as no new codes, subthemes or themes emerged from further interviews to explore the initial question. Clinical Practice Pregnancy Pregnancy is considered a major difficulty in clinical practice. Most participants expressed the utilization of an online French recommendation while observing a lack of knowledge. Taking care of pregnant women has been declared an anxious situation because of the potential risk of teratogenesis, and the sensation of undertreatment has been expressed. I feel there is a loss of chance, because we could prescribe better treatment. For example, for last generation anti psychotics, maybe we have… less safety evidence than Haloperidol or Chlorpromazine. J2 For pregnancy, I think level of evidence is weak or nonexistent […] therefor we often propose obsolete psychotherapy or medication. H2 The participants also reported being concerned with potential interactions with hormonal contraception, which could induce unexpected pregnancies when they are taking care of childbearing potential women. Gender considerations According to the participants, female hormonal variation is not commonly taken into account in daily practice in psychiatry either for symptoms or for reactivity to medications. I take care of teenagers and young adults… We don’t take puberty into account in our evaluation… Nobody does. M8 In psychiatry there are some specificities due to hormonal cycle of women […] we are not well trained especially on issue related to disorder that appear during menopause or premenstrual disorder. I5 Differences in symptoms have been highlighted for ASD and ADHD, which are considered for diagnosis, while the delay it can induce has been noted. [women] will have different type of restrictive interests […] girls will most often be interested in animals. These criteria may be incorrect for women. J2 (about ASD symptoms) Alcohol use disorder installation has been described with different patterns, with women presenting more solo daily drinking while being less tolerated by society. Nosology Nosology has been described as a tool by some participants with limitations. While considering it, they also expressed that getting some distance when the diagnosis enables positive outcomes such as social benefits. Research In general, the respondents were favorable toward the inclusion of women in research, including during pregnancy and breastfeeding. The respondents reported managing men and women equally during the inclusion process; however, they described the additional role of the Clinical Research Associate (CRA) during the protocol for women, as it controls the negativity of pregnancy tests. We need to have a weekly negative pregnancy test before beginning the session. It is a major concern for the clinical research associate he will not have for men. G8 Some participants reported not having control of the exclusion criteria, as they were part of umbrella protocols; therefore, they could not include pregnant or breastfeeding women. It is a general exclusion criteria as my research is part of a biggest one which included many others like a biological part this is why we can’t include pregnant women. S4 Pregnancy is an exclusion criterion […]. This is a national cohort […] I am just a part of it. M8 One participant has evoked epidemiological studies conducted on national databases populated from access to all health care procedures, considering this as more equal in inclusion. It could be a part of the solution, because every people having an appointment in the hospital will be added. It ensures a kind of equity in inclusion. I5 Ethics committee Interaction between French Research Ethics Committees (fRECs) and researchers Interaction with fREC is described as challenging for both times and administrative parts, and most participants described a delay of one year before receiving a validation for their protocol. The CRA was omnipresent in the relationship between the researcher and fREC. On the other hand, participants who had experiences in studies in foreign countries reported fewer implications of CRAs but more direct and collaborative interactions with RECs. It was truly burdensome, we were at the limit of an interventional protocol and we had to check as we were conducting a medication study. Goals of the ethical review board were unclear to us. […] What I am saying is everyone try to avoid fERB. We are going to prefer umbrella protocols which enabled faster studies I5 In fact, some participants have also declared that they anticipate potential refusals of the fREC by adding pregnant and not using contraceptive women in the exclusion criteria while considering this decision as an overprotection. As I had [request of adding pregnant and not using contraceptive women] twice, I think I just added pregnant and nonusing contraceptive as an exclusion criterion for every of my studies. I might have censored myself as I was thinking it will be asked. […] One was for psychotherapy one for RTMS, it was surreal, it didn’t make any sens. H2 Formation Most participants reported a lack of training in ethics, expressing disinterest in this subject during medical studies. During medical studies, we think there is more important subjects so, as a student, I did not consider the importance of these teaching. S4 The participants expressed regrets regarding their lack of knowledge of ethics but showed clear interest in the rationale of the study during informal discussions. The WHO and SAGER recommendations are unknown to researchers. Social interaction analysis in the context of French psychiatric research Our participants highlighted the additional role of the CRA during the inclusion of women in clinical psychiatry research. More generally, CRAs have been described as physical, bilateral and beneficial, as they work on the protocol together. Furthermore, researchers and CRAs are both involved in the process of subject inclusion in clinical studies for both men and women with similar goals. We decided to represent them as a social group. The relationship with the fREC is made through email and is anonymous; most researchers reported that the email relationship with the fREC was led by the CRA. We also represent potential research subjects as a group to enhance comprehension of the global goal of the relationship Fig. 2 . Lexicometric analysis We used the Reinert analysis to perform divisive hierarchical clustering (DHC) and correspondence analysis (AC). The DHC retrieves a dendogram with three homogeneous classes. The first class is composed of words directly related to the psychiatric field, the second with words related to women’s reproductive specificities, and the third is related to the ethics committee. According to the AC analysis, classes 1 and 2 cooccur in our participants' narratives, whereas class 3 is independently discussed. These results highlight the difficulties for researchers in integrating spontaneous ethical discussion with technical responses. These three classes overlapped our manual qualitative analysis. Both analyses are shown in Fig. 3 . Discussion We aimed to explore the experience of female inclusion by French psychiatrist researchers. In this study, pregnancy was considered challenging in clinical practice, whereas participants wanted to include women in their studies without restrictions regarding pregnancy, breastfeeding and not using contraceptive women. Relation with fREC is reported as difficult with negative representation while reporting a lack of interest in the ethical field. In general, 45% of pregnancies remain unexpected, with higher risks depending mainly on social status (25–27) ; as a consequence, women with chronic diseases will also present unexpected pregnancies. Women suffering from severe mental disorders present even higher rates of unexpected pregnancies and abortion (28), but their knowledge remains low, increasing their vulnerability. Psychiatric diseases present some specificities. While treatments for chronic psychiatric diseases present a high effect size, their numbers remain low, and for the most part, they have similar biological actions; consequently, therapeutic options are lower than those for other chronic diseases. In terms of symptoms, anosognosia, which is the inability to recognize one’s own condition, is specific to neurophysiological diseases. Small changes in the lifestyle of a stabilized patient can trigger a resurgence of symptoms, but in contrast to patients with nonphysiological diseases, patients may not seek help and may not realize their symptoms, leading to delays in treatment and recovery; in the case of a pregnant woman, these changes can potentially harm the fetus. Safety data for the prescription of medication during pregnancy are scarce during the first semester (29), whereas the number of prescriptions during pregnancy has increased in recent decades (30). The participants in this study focused on the use of antipsychotics (APs) during pregnancy in their responses. The last commercialized AP in France was aripiprazole in 2004. Aripiprazole is considered to induce fewer metabolic side effects than other APs do and is not associated with hyperprolactinemia, which induces reproductive impairments. French specific and international recommendations consider this medication safe during pregnancy (31,32); however, it is only based on retrospective data (33). Here, we highlight a potential dilemma for psychiatrists and society. Our respondents are aware of the lack of evidence during pregnancy and wish to increase specific knowledge. In early life, a medication, or intervention, might be prescribed to women who can become pregnant while being effectively treated due to the unexpected nature of pregnancy. In this situation, the individual responsibility of the psychiatrist, the direct potential harm to women or fetuses and the unpredictable reaction of switching the treatment to stabilization create a complex situation. Furthermore, while teratogenesis risks are foreseen during preclinical studies, pharmacokinetic and pharmacodynamic variations during pregnancy remain unknown until they are given to women. In this case, psychiatrists, researchers and society should answer the following questions: when do we want the risks of exposing pregnant women to new drugs to be taken: during clinical trials or in clinical practice? In another field, a similar question has already been addressed by the WHO for women suffering from infection by HIV: a paradigm switch must be made from exclusion to protection through research (30). This analysis is based on the risk associated with the absence of proof, as it remains impossible to prove a complete absence of risk; consequently, the WHO considers that the inclusion of pregnant and breastfeeding women must be enabled and promoted as early as possible. In medicine, the rank of evidence has been developed to provide guidelines for practitioners. The highest rank is based on realization of randomized control trials (RCTs), as it remains the most efficient way to minimize bias. One participant mentioned the role of epidemiological studies as a solution for underrepresentation. Indeed, epidemiological, retrospective and phase four studies could provide different inclusion patterns with their own advantages and downsides, but they remain more sensible to bias and are not considered valuable for the highest rank in the gradation of guidelines for both Cochrane and the world journal of biological psychiatry grading system (35,36). In this situation, the underrepresentation of women in RCTs has led to a gap in evidence between men and women, which cannot, with our actual system of gradation, be fulfilled by other types of studies. Some could argue that, considering the precaution principle, studies on childbearing potential women should be conducted after those on men to protect both pregnant women and potential fetuses. It is, from our point of view, a misinterpretation of this principle. Developed by Hans Jonas in 1979 in the context of climatic change, it was added to the French constitution in 2000 (37). It includes two main prevention measures: predetermined monitoring of variables to evaluate the impact of the intervention and exit strategies if a variable threshold has been reached with specific actions to minimize its impact in the long term. However, the excessive application of this principle can result in precautionism when it is used to block any possibility of innovation or change. Systematic exclusion of women in clinical trials after the thalidomide crisis can be seen as an overuse of precaution and may, in itself, induce specific harm to the population. Consequently, Claude Sureau proposed developing the concept of “precaution ethic”, which would integrate the mandatory incertitude in medical practice (38). In psychiatry, the prescription of clozapine can be seen as a usage of this concept; it has been retired from the market because of its high potential mortality side effects but was reintroduced with careful monitoring, as its beneficial effects are high for patients. This close monitoring has enabled the production of gender and ethnicity recommendations for dosing on the basis of mandatory blood concentration controls. However, monitoring can be considered too restrictive and has led to underutilization of clozapine in several countries, including France (39,40). The balance remains difficult to find and is always perfectible; defining a precaution ethic should be collaborative and adaptive. While considering the lack of specific knowledge about women, researchers have also declared, for the most part, that they are unable to control the inclusion and exclusion criteria. The main reason evoked was being part of an umbrella protocol. As we described, fRECs tend to review protocols over a long delay, which has been considered a downside from French psychiatrist researchers, leading to the promotion of umbrella protocols to cover multiple planned or upcoming studies. In this case, future participants must be protected from every possible study included in this protocol, which may cancel the participation of pregnant, breastfeeding or nonusing contraceptive women, as described by our participants. In our study, we considered large exclusion criteria concerning contraception for which researchers did not agree during the interview, considering that enough safety data were available at the time to include all women. These were either added by researchers prior to submission or asked by the fREC and may lead to the inclusion of an unrepresentative population in psychiatric studies. In this case, participants and society may be exposed to an overrisk without beneficial outcomes, as the targeted and included populations may diverge. The interest in the inclusion of women in studies and the change in paradigm remain recent. A recent article proposed some evolution for the role of REC in the inclusion of women in clinical trials: exclusion criteria have to be justified for pregnant and breastfeeding women, and in the case of potential inclusion of pregnant or breastfeeding women, additional feedback provided to ethics boards has been proposed as a safety procedure (41). According to the WHO recommendations, the inclusion of childbearing potential women should be foreseen before submission to the fREC, and specific information letters for women should be drafted with information about risks for potential pregnancy or incidence. By following these recommendations, researchers could enhance their understanding of REC and avoid being frustrated by refusals they consider as an over-evaluation of risk. However, the fREC should be legitimately asked for an explanation of the systematic exclusion of nonusing contraceptive women and the potential impact of the intervention on pregnancy, considering that once it has been legally approved, unexpected pregnancies will be discovered during exposure. The relationship between researchers and fREC is indirect and distant. Email-based communication has been shown to create incomprehension, as it can exclude social cues and nonverbal communication(42). Considering the lack of knowledge reported by our participants, from our point of view, this is the breeding ground of the negative opinion shared in this study. Formations about REC roles to french psychiatrists could enhance comprehension from researchers of the objectives that lead fREC decisions. A recent article published by an Australian ethicist (43) summarized the criticisms made on the ethical review process over the years. In our study, we retrieved all the main criticism reported: difficulties in communication, administrative challenges, a lack of comprehension of the ethics board goal, the sensation that the fREC is a “gatekeeper” and the overestimation of risk. They also presented some propositions to enhance comprehension and collaboration. They proposed creating more direct communication between the board and the researchers with an “officer” that would be a human interface. In France, submission for ethical review has been made through a national platform since 2018 (44); the review board is randomly selected, and communication is made through this numeric platform. In our study, the CRA was presented as omnipresent in interactions with the REC, and for some researchers, communications with the fREC occurred only through the CRA. Despite this additional human interface, negative opinions of REC persist. Consequently, and according to our results, the “officer” will have to address three communicants: the REC, the CRA and the researcher. This adds complexity to the global situation and may be an obstacle to its efficiency if it is implemented in France. However, other propositions, particularly the intervention of fREC members by psychiatrists and increased interest in medical studies, could represent a way of addressing the negative opinions shared in this study. Our study has several strengths. We included participants from different workplaces with different experiences. We did reach theoretical data saturation for our primary research question. While we did not obtain a high number of participants, our research question was restrained, and the selection of samples was highly homogeneous, which concurs with the data saturation (45). The theme “ethics committee” was introduced deductively from the first two interviews. The post hoc lexocimetric analysis corroborates the qualitative analysis conducted. The results of our study concur with those of international bibliographies. Our study has several limitations. Data analysis was performed by only one author (FB). We did not triangulate our data and did not address transcription to participants prior to analysis. Our sociogram is not based on observations but rather on reports made by researchers and may not reflect reality. Conclusion According to our analysis of French psychiatrist interviews, the inclusion of women in psychiatric studies is closely related to pregnancy. The following barriers to inclusion have been identified: umbrella protocols, delays in protocol validation and anticipation of refusals, which are grounded in the incomprehension of the goal of fREC by researchers. The promotion of women’s inclusion in psychiatry research is needed to address this negative vision. Additionally, enhancing communication and faster review by fRECs could facilitate the promotion of women’s inclusion. However, these relationships remain complex, and further research should be conducted to address the experiences of women during studies and members of the fREC to complete and confront the analysis performed in this study. Declarations Ethics approval and consent to participate : Ethical approval was granted by Comité d'éthique de la recherche APHP France N° IORG0010044. This study was conducted in accordance with the principles of the Declaration of Helsinki. Acknowledgements : We would like to thank all participants for their time and implication Authors' contributions : FB initiated the study, collected data, realized analysis and drafted the manuscript. FR and ALJ revised the manuscript and provided substantial corrections. FR overviewed the realization of the semi-quantitative analysis. Funding : No financial support was asked for this study. Competing interests : All authors declared not having competing interests. Availability of data and materials : The datasets generated and analysed during the current study are not publicly available, but anonymized excerpts may be available from the corresponding author on reasonable request. Consent for publication : All participants provided informed consent prior to participation. They were made aware of the study’s purpose, procedures, and potential risks or benefits. 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WFSBP guidelines on how to grade treatment evidence for clinical guideline development. The World Journal of Biological Psychiatry. 2019 Jan 2;20(1):2–16. Welcome | Cochrane GRADEing [Internet]. [cited 2024 Aug 24]. Available from: https://methods.cochrane.org/gradeing/ Larrère C. Le principe de précaution et ses critiques. Innovations. 2003;18(2):9–26. Sureau C. « Principe de précaution » ou « éthique de précaution » ?L’activité médicale et le principe de précaution. Les Cahiers du Centre Georges Canguilhem. 2009;3(1):41–55. Bogers JPAM, Schulte PFJ, Van Dijk D, Bakker B, Cohen D. Clozapine Underutilization in the Treatment of Schizophrenia: How Can Clozapine Prescription Rates Be Improved? Journal of Clinical Psychopharmacology. 2016 Apr;36(2):109. Kelly DL, Freudenreich O, Sayer MA, Love RC. Addressing Barriers to Clozapine Underutilization: A National Effort. PS. 2018 Feb;69(2):224–7. Payne P. Including Pregnant Women in Clinical Research: Practical Guidance for Institutional Review Boards. Ethics & Human Research. 2019;41(6):35–40. Sproull L, Kiesler S. Reducing Social Context Cues: Electronic Mail in Organizational Communication. Management Science. 1988 Jan 1;32:1492–512. Hickey A, Davis S, Farmer W, Dawidowicz J, Moloney C, Lamont-Mills A, et al. Beyond Criticism of Ethics Review Boards: Strategies for Engaging Research Communities and Enhancing Ethical Review Processes. J Acad Ethics. 2022 Dec 1;20(4):549–67. Ministère du travail, de la santé et des solidarités [Internet]. [cited 2024 Aug 25]. Le tirage au sort du Comité de protection des personnes (CPP). Available from: https://sante.gouv.fr/systeme-de-sante/innovation-et-recherche/recherche-impliquant-la-personne-humaine/foire-aux-questions/article/le-tirage-au-sort-du-comite-de-protection-des-personnes-cpp Hennink M, Kaiser BN. Sample sizes for saturation in qualitative research: A systematic review of empirical tests. Social Science & Medicine. 2022 Jan 1;292:114523. Additional Declarations No competing interests reported. Supplementary Files BMCCOREQChecklist.pdf 20250521BMCMEappendix.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6718965","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":466885012,"identity":"b9bdda1c-7770-41b3-970f-7614cda10acf","order_by":0,"name":"François Berthet","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYBAC9hlAgrGBgYEfwpcjrIXnBpA42MAgIdkA5huToMXgANFapJuPff64w6bO+Nrxi48LGAzyCWuROZY84+CZNAmz2znFxjMYDCwbCGmxl8gxZjjYdhikJU2ah+GPAWFbJPI/A7X8lzCenZP+m4fBgBgtOcxALQckDKTTjzETp0XmmDHD2bZkyRm3c5ileQyI0SLd/Jihss2On392+sPPPBVEaEHWDVRNkgZg2nlAmvpRMApGwSgYMQAAYL83+ReGiuAAAAAASUVORK5CYII=","orcid":"","institution":"MGEN Action sanitaire et sociale - groupe VYV, Établissement de Santé Mentale de Rueil-Malmaison","correspondingAuthor":true,"prefix":"","firstName":"François","middleName":"","lastName":"Berthet","suffix":""},{"id":466885013,"identity":"a21e6c9d-2550-442c-8828-7d74ac6c2d5b","order_by":1,"name":"Anne Le Jeannic","email":"","orcid":"","institution":"MGEN Action sanitaire et sociale - groupe VYV, Établissement de Santé Mentale de Rueil-Malmaison","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"Le","lastName":"Jeannic","suffix":""},{"id":466885014,"identity":"0de7d23d-e30a-4fd3-9ac9-bbfcaa39c8c2","order_by":2,"name":"Franck Rolland","email":"","orcid":"","institution":"MGEN Action sanitaire et sociale - groupe VYV, Établissement de Santé Mentale de Rueil-Malmaison","correspondingAuthor":false,"prefix":"","firstName":"Franck","middleName":"","lastName":"Rolland","suffix":""}],"badges":[],"createdAt":"2025-05-21 18:38:10","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6718965/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6718965/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85618162,"identity":"243ff88e-2504-43dd-ac55-716ffe161292","added_by":"auto","created_at":"2025-06-29 14:49:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23677,"visible":true,"origin":"","legend":"\u003cp\u003eCoding tree; themes and subthemes\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6718965/v1/bfb5a5590d7813030866f5e0.png"},{"id":85618166,"identity":"62bec54b-a407-4b4c-8e39-edefde86b85e","added_by":"auto","created_at":"2025-06-29 14:49:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21041,"visible":true,"origin":"","legend":"\u003cp\u003eSociogram relation between between researchers, CRA, fREC and potential subjects, based on participant’s account. Single way arrow : unilateral relation; double ways arrow bilateral relation; continuous line : physical relation; double dash line : pregnancy test surveillance; dash line : email communication; dot line : ethic based protection\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6718965/v1/dd860ebc1acd2e6c7cede59c.png"},{"id":85619314,"identity":"1b9b8cf5-171a-4dbc-bfe0-30b6d8f03a1b","added_by":"auto","created_at":"2025-06-29 14:57:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":17244,"visible":true,"origin":"","legend":"\u003cp\u003eLexicometric analysis of interviews. Left : Divisive Hierarchical Clustering; Right: Correspondence Analysis\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6718965/v1/5d34c0abaaa034ba5a713138.png"},{"id":91810340,"identity":"d7bf01f5-15ce-4c78-834d-efc25194fb36","added_by":"auto","created_at":"2025-09-22 04:16:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":622900,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6718965/v1/d215d9d0-d3e2-469c-b855-af84e4876576.pdf"},{"id":85619311,"identity":"fb1d8c8c-7ae3-4aab-bde3-d3a0f3c313c8","added_by":"auto","created_at":"2025-06-29 14:57:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":604120,"visible":true,"origin":"","legend":"","description":"","filename":"BMCCOREQChecklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6718965/v1/456265556c10e36a3690e719.pdf"},{"id":85618164,"identity":"8d8af6fd-c1d5-4d78-97a2-d0d8c63350ee","added_by":"auto","created_at":"2025-06-29 14:49:07","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6304,"visible":true,"origin":"","legend":"","description":"","filename":"20250521BMCMEappendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-6718965/v1/c2228a8e37f05e9dcf1f2876.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Inclusion of Women in French Psychiatric Clinical Trials: A Qualitative Study of Researchers’ Experiences and Challenges","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFor decades, women and, more generally, female sex has been underrepresented in biomedical research, leading to inequalities in knowledge (1). Following the Thalidomide crisis, the Food and Drug Administration (FDA) has excluded childbearing potential women from early dosing studies since 1977 (2). Consequently, women were not included until the phase 3 trial. However, during the HIV epidemic, evidence emerged that women react differently than men do: a longer incubation time, worse tolerance and greater efficiency of treatment (3) led to a new law, voted upon by the American Congress in 1993: the inclusion of women and minorities became mandatory to gain access to financial support from the National Institute of Health. On the other hand, preclinical studies also present inequalities in sex representation, leading to greater side effects for women, which could have been foreseen (4). For example, the dosage of the drug zolpidem has been adapted by sex 10 years after it was commercialized by the FDA due to increased reports of side effects in women secondary to a half-life in blood two times greater than those in men \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e(5\u0026ndash;7)\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eFurthermore, underrepresentation of female sex can lead to misdiagnosis and treatment of specific diseases, such as myocardial infarction, as their clinical presentation and pathophysiology differ from those of men (7,8). With respect to this underrepresentation, the World Health Organization (WHO) published guidelines for health-related research in humans in 2016 (9). Two chapters of these guidelines focus on women\u0026rsquo;s inclusion, in which the systematic exclusion of women after the Thalidomide crisis is considered problematic. While considering the potential vulnerability of women during clinical studies, it must be considered an extrinsic factor that is based mainly on society and lacks specific knowledge (10). In Europe, the editorial board of the Lancet has produced specific guidelines for authors to consider gender in studies (11).\u003c/p\u003e \u003cp\u003eIn psychiatry and neurophysiology, increasing evidence highlights the importance of gender considerations in research and clinical practice: women present more resistance to antidepressants, specific patterns of consumption when dealing with cocaine addiction, different ages of schizophrenia onset, and twofold greater risks of developing Alzheimer\u0026rsquo;s disease (12\u0026ndash;15); furthermore, a recent publication revealed the potential role of estrogens as a treatment for psychiatric disease for women (16). In France, decades of effort in women\u0026rsquo;s cancer research have been made through the E3N cohort, enabling high-quality studies on women\u0026rsquo;s health (17,18). However, the specificities of women\u0026rsquo;s mental health in France have been mainly unaddressed by the Senatorial Commission of 2015 (19). In 2023, a report produced by French deputes on women\u0026rsquo;s mental health recommended equal inclusion of both genders in psychiatric biomedical studies, but it remains lightly justified (20).\u003c/p\u003e \u003cp\u003eIn this context of the global underrepresentation of women in biomedical research and the recent awareness in the French psychiatric field, we propose to answer the following question: According to French psychiatrists, what are the factors that promote or impede the inclusion of women in biomedical research?\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting\u003c/h2\u003e \u003cp\u003eWe performed exploratory qualitative research among French psychiatrists with active research activities. The study was designed by FB. FB realized the semiquantitative analysis, and FR overviewed it. FB drafted the manuscript, and FR and ALJ reviewed the manuscript providing substancial corrections. FB is a male psychiatrist with experience in quantitative research who is conducting his first qualitative research for a master\u0026rsquo;s degree. FR is a male psychiatrist with a master\u0026rsquo;s degree in the ethics field with experience in qualitative research. ALJ is a female psychiatrist. Semistructured interviews (SSIs) were conducted by FB. The initial interview guide was developed specifically for this study based on a review of the relevant literature and was adapted iteratively as themes emerged during the interviews. The final version of the guide is provided in the appendix. An email was sent to the participants describing the subject, field of research and professional status of FBs; in the absence of response, a second email was sent 15 days later. First, emails were sent by convenience, after which snowball sampling methodology was used: participants were asked two potential participants. At the end of the SSI, an informal conversation was initiated. This research was approved by an ethics committee. The manuscript has been drafted according to the 32 items of the COREQ checklist (20).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eSSI was conducted privately once at the workplace of the participant. Consent was audio-recorded at the beginning of the interview. One interview was 30 minutes long, the majority lasted one hour, and field notes were taken. Data were collected between February and May 2024.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eAudio data were transcribed and received a random code with one letter and one number. A table was created with the code and participant characteristics, and then the transcriptions were deidentified before analysis. Themes were generated deductively from the literature and inductively on the basis of grounded theory (21). Analysis was performed with Taguette, an open source software (22), by FB. The quotation has been translated to English by FB. All the interviews were analyzed. The sociogram presented in the results section was created according to Moreno theory (23). A lexicometric analysis was performed with Iramuteq (24) after the qualitative analysis ended. Deidentified transcriptions were united in one file, with the exclusion of informal discussions, and individual interviews were used as variables for analysis. We used the default parameters proposed by the software.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-nine potential participants were contacted, most of whom did not respond after the second email. Ten agreed to participate, but three canceled their participation. The participants\u0026rsquo; ages ranged between 29 and 50 years, with 3 males and 4 womens. The field of studies conducted by participants was large (schizophrenia, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and addiction), with a variety of methodologies (fMRI, psychotherapy and transcranial stimulation). Three participants reported conducting studies in foreign countries. One participant knew the interviewer, as they had worked together for half a year. The results of the qualitative analysis are presented in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The \u0026ldquo;Ethics committee\u0026rdquo; theme emerged from grounded theory: it has deductively emerged from the first interview and was confirmed by the second. Data saturation was reached after the fourth interview, as no new codes, subthemes or themes emerged from further interviews to explore the initial question.\u003c/p\u003e\n\u003ch3\u003eClinical Practice\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003ePregnancy\u003c/h2\u003e\n \u003cp\u003ePregnancy is considered a major difficulty in clinical practice. Most participants expressed the utilization of an online French recommendation while observing a lack of knowledge. Taking care of pregnant women has been declared an anxious situation because of the potential risk of teratogenesis, and the sensation of undertreatment has been expressed.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eI feel there is a loss of chance, because we could prescribe better treatment. For example, for last generation anti psychotics, maybe we have\u0026hellip; less safety evidence than Haloperidol or Chlorpromazine. J2\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eFor pregnancy, I think level of evidence is weak or nonexistent [\u0026hellip;] therefor we often propose obsolete psychotherapy or medication. H2\u003c/em\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe participants also reported being concerned with potential interactions with hormonal contraception, which could induce unexpected pregnancies when they are taking care of childbearing potential women.\u003c/p\u003e\n\u003ch3\u003eGender considerations\u003c/h3\u003e\n\u003cp\u003eAccording to the participants, female hormonal variation is not commonly taken into account in daily practice in psychiatry either for symptoms or for reactivity to medications.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eI take care of teenagers and young adults\u0026hellip; We don\u0026rsquo;t take puberty into account in our evaluation\u0026hellip; Nobody does. M8\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIn psychiatry there are some specificities due to hormonal cycle of women [\u0026hellip;] we are not well trained especially on issue related to disorder that appear during menopause or premenstrual disorder. I5\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDifferences in symptoms have been highlighted for ASD and ADHD, which are considered for diagnosis, while the delay it can induce has been noted.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e[women] will have different type of restrictive interests [\u0026hellip;] girls will most often be interested in animals. These criteria may be incorrect for women. J2 (about ASD symptoms)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAlcohol use disorder installation has been described with different patterns, with women presenting more solo daily drinking while being less tolerated by society.\u003c/p\u003e\n\u003ch3\u003eNosology\u003c/h3\u003e\n\u003cp\u003eNosology has been described as a tool by some participants with limitations. While considering it, they also expressed that getting some distance when the diagnosis enables positive outcomes such as social benefits.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eResearch\u003c/h2\u003e\n \u003cp\u003eIn general, the respondents were favorable toward the inclusion of women in research, including during pregnancy and breastfeeding. The respondents reported managing men and women equally during the inclusion process; however, they described the additional role of the Clinical Research Associate (CRA) during the protocol for women, as it controls the negativity of pregnancy tests.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eWe need to have a weekly negative pregnancy test before beginning the session. It is a major concern for the clinical research associate he will not have for men. G8\u003c/em\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eSome participants reported not having control of the exclusion criteria, as they were part of umbrella protocols; therefore, they could not include pregnant or breastfeeding women.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIt is a general exclusion criteria as my research is part of a biggest one which included many others like a biological part this is why we can\u0026rsquo;t include pregnant women. S4\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePregnancy is an exclusion criterion [\u0026hellip;]. This is a national cohort [\u0026hellip;] I am just a part of it. M8\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOne participant has evoked epidemiological studies conducted on national databases populated from access to all health care procedures, considering this as more equal in inclusion.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIt could be a part of the solution, because every people having an appointment in the hospital will be added. It ensures a kind of equity in inclusion. I5\u003c/em\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eEthics committee\u003c/h2\u003e\n \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\n \u003ch2\u003eInteraction between French Research Ethics Committees (fRECs) and researchers\u003c/h2\u003e\n \u003cp\u003eInteraction with fREC is described as challenging for both times and administrative parts, and most participants described a delay of one year before receiving a validation for their protocol. The CRA was omnipresent in the relationship between the researcher and fREC. On the other hand, participants who had experiences in studies in foreign countries reported fewer implications of CRAs but more direct and collaborative interactions with RECs.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eIt was truly burdensome, we were at the limit of an interventional protocol and we had to check as we were conducting a medication study. Goals of the ethical review board were unclear to us. [\u0026hellip;] What I am saying is everyone try to avoid fERB. We are going to prefer umbrella protocols which enabled faster studies I5\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eIn fact, some participants have also declared that they anticipate potential refusals of the fREC by adding pregnant and not using contraceptive women in the exclusion criteria while considering this decision as an overprotection.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eAs I had [request of adding pregnant and not using contraceptive women] twice, I think I just added pregnant and nonusing contraceptive as an exclusion criterion for every of my studies. I might have censored myself as I was thinking it will be asked. [\u0026hellip;] One was for psychotherapy one for RTMS, it was surreal, it didn\u0026rsquo;t make any sens. H2\u003c/em\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003eFormation\u003c/h2\u003e\n \u003cp\u003eMost participants reported a lack of training in ethics, expressing disinterest in this subject during medical studies.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eDuring medical studies, we think there is more important subjects so, as a student, I did not consider the importance of these teaching. S4\u003c/em\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eThe participants expressed regrets regarding their lack of knowledge of ethics but showed clear interest in the rationale of the study during informal discussions. The WHO and SAGER recommendations are unknown to researchers.\u003c/p\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003eSocial interaction analysis in the context of French psychiatric research\u003c/h2\u003e\n \u003cp\u003eOur participants highlighted the additional role of the CRA during the inclusion of women in clinical psychiatry research. More generally, CRAs have been described as physical, bilateral and beneficial, as they work on the protocol together. Furthermore, researchers and CRAs are both involved in the process of subject inclusion in clinical studies for both men and women with similar goals. We decided to represent them as a social group. The relationship with the fREC is made through email and is anonymous; most researchers reported that the email relationship with the fREC was led by the CRA. We also represent potential research subjects as a group to enhance comprehension of the global goal of the relationship Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eLexicometric analysis\u003c/h2\u003e\n \u003cp\u003eWe used the Reinert analysis to perform divisive hierarchical clustering (DHC) and correspondence analysis (AC). The DHC retrieves a dendogram with three homogeneous classes. The first class is composed of words directly related to the psychiatric field, the second with words related to women\u0026rsquo;s reproductive specificities, and the third is related to the ethics committee. According to the AC analysis, classes 1 and 2 cooccur in our participants\u0026apos; narratives, whereas class 3 is independently discussed. These results highlight the difficulties for researchers in integrating spontaneous ethical discussion with technical responses. These three classes overlapped our manual qualitative analysis. Both analyses are shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe aimed to explore the experience of female inclusion by French psychiatrist researchers. In this study, pregnancy was considered challenging in clinical practice, whereas participants wanted to include women in their studies without restrictions regarding pregnancy, breastfeeding and not using contraceptive women. Relation with fREC is reported as difficult with negative representation while reporting a lack of interest in the ethical field.\u003c/p\u003e \u003cp\u003eIn general, 45% of pregnancies remain unexpected, with higher risks depending mainly on social status \u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003e(25\u0026ndash;27)\u003c/span\u003e; as a consequence, women with chronic diseases will also present unexpected pregnancies. Women suffering from severe mental disorders present even higher rates of unexpected pregnancies and abortion (28), but their knowledge remains low, increasing their vulnerability. Psychiatric diseases present some specificities. While treatments for chronic psychiatric diseases present a high effect size, their numbers remain low, and for the most part, they have similar biological actions; consequently, therapeutic options are lower than those for other chronic diseases. In terms of symptoms, anosognosia, which is the inability to recognize one\u0026rsquo;s own condition, is specific to neurophysiological diseases. Small changes in the lifestyle of a stabilized patient can trigger a resurgence of symptoms, but in contrast to patients with nonphysiological diseases, patients may not seek help and may not realize their symptoms, leading to delays in treatment and recovery; in the case of a pregnant woman, these changes can potentially harm the fetus.\u003c/p\u003e \u003cp\u003eSafety data for the prescription of medication during pregnancy are scarce during the first semester (29), whereas the number of prescriptions during pregnancy has increased in recent decades (30). The participants in this study focused on the use of antipsychotics (APs) during pregnancy in their responses. The last commercialized AP in France was aripiprazole in 2004. Aripiprazole is considered to induce fewer metabolic side effects than other APs do and is not associated with hyperprolactinemia, which induces reproductive impairments. French specific and international recommendations consider this medication safe during pregnancy (31,32); however, it is only based on retrospective data (33). Here, we highlight a potential dilemma for psychiatrists and society. Our respondents are aware of the lack of evidence during pregnancy and wish to increase specific knowledge. In early life, a medication, or intervention, might be prescribed to women who can become pregnant while being effectively treated due to the unexpected nature of pregnancy. In this situation, the individual responsibility of the psychiatrist, the direct potential harm to women or fetuses and the unpredictable reaction of switching the treatment to stabilization create a complex situation. Furthermore, while teratogenesis risks are foreseen during preclinical studies, pharmacokinetic and pharmacodynamic variations during pregnancy remain unknown until they are given to women. In this case, psychiatrists, researchers and society should answer the following questions: when do we want the risks of exposing pregnant women to new drugs to be taken: during clinical trials or in clinical practice? In another field, a similar question has already been addressed by the WHO for women suffering from infection by HIV: a paradigm switch must be made from exclusion to protection through research (30). This analysis is based on the risk associated with the absence of proof, as it remains impossible to prove a complete absence of risk; consequently, the WHO considers that the inclusion of pregnant and breastfeeding women must be enabled and promoted as early as possible. In medicine, the rank of evidence has been developed to provide guidelines for practitioners. The highest rank is based on realization of randomized control trials (RCTs), as it remains the most efficient way to minimize bias. One participant mentioned the role of epidemiological studies as a solution for underrepresentation. Indeed, epidemiological, retrospective and phase four studies could provide different inclusion patterns with their own advantages and downsides, but they remain more sensible to bias and are not considered valuable for the highest rank in the gradation of guidelines for both Cochrane and the world journal of biological psychiatry grading system (35,36). In this situation, the underrepresentation of women in RCTs has led to a gap in evidence between men and women, which cannot, with our actual system of gradation, be fulfilled by other types of studies.\u003c/p\u003e \u003cp\u003eSome could argue that, considering the precaution principle, studies on childbearing potential women should be conducted after those on men to protect both pregnant women and potential fetuses. It is, from our point of view, a misinterpretation of this principle. Developed by Hans Jonas in 1979 in the context of climatic change, it was added to the French constitution in 2000 (37). It includes two main prevention measures: predetermined monitoring of variables to evaluate the impact of the intervention and exit strategies if a variable threshold has been reached with specific actions to minimize its impact in the long term. However, the excessive application of this principle can result in precautionism when it is used to block any possibility of innovation or change. Systematic exclusion of women in clinical trials after the thalidomide crisis can be seen as an overuse of precaution and may, in itself, induce specific harm to the population.\u003c/p\u003e \u003cp\u003eConsequently, Claude Sureau proposed developing the concept of \u0026ldquo;precaution ethic\u0026rdquo;, which would integrate the mandatory incertitude in medical practice (38). In psychiatry, the prescription of clozapine can be seen as a usage of this concept; it has been retired from the market because of its high potential mortality side effects but was reintroduced with careful monitoring, as its beneficial effects are high for patients. This close monitoring has enabled the production of gender and ethnicity recommendations for dosing on the basis of mandatory blood concentration controls. However, monitoring can be considered too restrictive and has led to underutilization of clozapine in several countries, including France (39,40). The balance remains difficult to find and is always perfectible; defining a precaution ethic should be collaborative and adaptive.\u003c/p\u003e \u003cp\u003eWhile considering the lack of specific knowledge about women, researchers have also declared, for the most part, that they are unable to control the inclusion and exclusion criteria. The main reason evoked was being part of an umbrella protocol. As we described, fRECs tend to review protocols over a long delay, which has been considered a downside from French psychiatrist researchers, leading to the promotion of umbrella protocols to cover multiple planned or upcoming studies. In this case, future participants must be protected from every possible study included in this protocol, which may cancel the participation of pregnant, breastfeeding or nonusing contraceptive women, as described by our participants. In our study, we considered large exclusion criteria concerning contraception for which researchers did not agree during the interview, considering that enough safety data were available at the time to include all women. These were either added by researchers prior to submission or asked by the fREC and may lead to the inclusion of an unrepresentative population in psychiatric studies. In this case, participants and society may be exposed to an overrisk without beneficial outcomes, as the targeted and included populations may diverge.\u003c/p\u003e \u003cp\u003eThe interest in the inclusion of women in studies and the change in paradigm remain recent. A recent article proposed some evolution for the role of REC in the inclusion of women in clinical trials: exclusion criteria have to be justified for pregnant and breastfeeding women, and in the case of potential inclusion of pregnant or breastfeeding women, additional feedback provided to ethics boards has been proposed as a safety procedure (41). According to the WHO recommendations, the inclusion of childbearing potential women should be foreseen before submission to the fREC, and specific information letters for women should be drafted with information about risks for potential pregnancy or incidence. By following these recommendations, researchers could enhance their understanding of REC and avoid being frustrated by refusals they consider as an over-evaluation of risk. However, the fREC should be legitimately asked for an explanation of the systematic exclusion of nonusing contraceptive women and the potential impact of the intervention on pregnancy, considering that once it has been legally approved, unexpected pregnancies will be discovered during exposure.\u003c/p\u003e \u003cp\u003eThe relationship between researchers and fREC is indirect and distant. Email-based communication has been shown to create incomprehension, as it can exclude social cues and nonverbal communication(42). Considering the lack of knowledge reported by our participants, from our point of view, this is the breeding ground of the negative opinion shared in this study. Formations about REC roles to french psychiatrists could enhance comprehension from researchers of the objectives that lead fREC decisions. A recent article published by an Australian ethicist (43) summarized the criticisms made on the ethical review process over the years. In our study, we retrieved all the main criticism reported: difficulties in communication, administrative challenges, a lack of comprehension of the ethics board goal, the sensation that the fREC is a \u0026ldquo;gatekeeper\u0026rdquo; and the overestimation of risk. They also presented some propositions to enhance comprehension and collaboration. They proposed creating more direct communication between the board and the researchers with an \u0026ldquo;officer\u0026rdquo; that would be a human interface. In France, submission for ethical review has been made through a national platform since 2018 (44); the review board is randomly selected, and communication is made through this numeric platform. In our study, the CRA was presented as omnipresent in interactions with the REC, and for some researchers, communications with the fREC occurred only through the CRA. Despite this additional human interface, negative opinions of REC persist. Consequently, and according to our results, the \u0026ldquo;officer\u0026rdquo; will have to address three communicants: the REC, the CRA and the researcher. This adds complexity to the global situation and may be an obstacle to its efficiency if it is implemented in France. However, other propositions, particularly the intervention of fREC members by psychiatrists and increased interest in medical studies, could represent a way of addressing the negative opinions shared in this study.\u003c/p\u003e \u003cp\u003eOur study has several strengths. We included participants from different workplaces with different experiences. We did reach theoretical data saturation for our primary research question. While we did not obtain a high number of participants, our research question was restrained, and the selection of samples was highly homogeneous, which concurs with the data saturation (45). The theme \u0026ldquo;ethics committee\u0026rdquo; was introduced deductively from the first two interviews. The post hoc lexocimetric analysis corroborates the qualitative analysis conducted. The results of our study concur with those of international bibliographies.\u003c/p\u003e \u003cp\u003eOur study has several limitations. Data analysis was performed by only one author (FB). We did not triangulate our data and did not address transcription to participants prior to analysis. Our sociogram is not based on observations but rather on reports made by researchers and may not reflect reality.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAccording to our analysis of French psychiatrist interviews, the inclusion of women in psychiatric studies is closely related to pregnancy. The following barriers to inclusion have been identified: umbrella protocols, delays in protocol validation and anticipation of refusals, which are grounded in the incomprehension of the goal of fREC by researchers. The promotion of women\u0026rsquo;s inclusion in psychiatry research is needed to address this negative vision. Additionally, enhancing communication and faster review by fRECs could facilitate the promotion of women\u0026rsquo;s inclusion. However, these relationships remain complex, and further research should be conducted to address the experiences of women during studies and members of the fREC to complete and confront the analysis performed in this study.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate :\u003c/strong\u003e Ethical approval was granted by Comit\u0026eacute; d\u0026apos;\u0026eacute;thique de la recherche APHP France N\u0026deg; IORG0010044. This study was conducted in accordance with the principles of the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements :\u0026nbsp;\u003c/strong\u003eWe would like to thank all participants for their time and implication\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions :\u003c/strong\u003e FB initiated the study, collected data, realized analysis and drafted the manuscript. FR and ALJ revised the manuscript and provided substantial corrections. FR overviewed the realization of the semi-quantitative analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding :\u0026nbsp;\u003c/strong\u003eNo financial support was asked for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests :\u0026nbsp;\u003c/strong\u003eAll authors declared not having competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials :\u003c/strong\u003e The datasets generated and analysed during the current study are not publicly available, but anonymized excerpts may be available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication :\u003c/strong\u003e All participants provided informed consent prior to participation. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://sante.gouv.fr/systeme-de-sante/innovation-et-recherche/recherche-impliquant-la-personne-humaine/foire-aux-questions/article/le-tirage-au-sort-du-comite-de-protection-des-personnes-cpp\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003eHennink M, Kaiser BN. Sample sizes for saturation in qualitative research: A systematic review of empirical tests. Social Science \u0026amp; Medicine. 2022 Jan 1;292:114523.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"terms, ethics research, gender role, psychiatry","lastPublishedDoi":"10.21203/rs.3.rs-6718965/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6718965/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Since the thalidomide crisis, women have been underrepresented in clinical studies, leading to inequalities in knowledge and clinical consequences. International recommendations promoting women’s inclusion and gender consideration by the World Health Organization (WHO) and the Lancet Group highlight the recent increase in awareness. There is growing evidence that gender is a central factor in neurophysiological and psychiatric disorders in all aspects. In France, these specificities have been mainly unaddressed.\u003c/p\u003e\n\u003cp\u003eMethods: We performed seven semistructured interviews with French psychiatrist researchers. Qualitative analysis was performed, and themes and subthemes were generated deductively on the basis of bibliography inductively via grounded theory. Semiquantitative analysis was performed via Iramuteq software.\u003c/p\u003e\n\u003cp\u003eResults: In clinical practice, taking care of pregnant women is considered an anxious situation, as the safety of treatment is considered uncertain. The participants were favorable toward women inclusion without limitations. Clinical research associates are more burdened when dealing with the inclusion of women than with that of men. Relation with research ethics committees (RECs) is described as challenging, leading to the implementation of umbrella protocols and expecting refusals to include pregnant, breastfeeding and nonusing contraceptive women.\u003c/p\u003e\n\u003cp\u003eDiscussion: Underrepresentation of women in clinical trials in psychiatry has led to a gap in knowledge that cannot be filled by retrospective studies. Switching the paradigm from protection from research to protection through participation, as proposed by the WHO, could address this gap. We argue that biomedical research should move beyond the rigid application of the precautionary principle and adopt a precaution ethics approach, which acknowledges that lack of evidence can itself generate ethical risk. The fluctuation of anosognosia, which is specific to psychiatric diseases, may expose pregnant women to not seek help when they are experiencing a resurgence of symptoms. Criticisms made on French REC concur with international literature. Improving education in research ethics and facilitating communication between RECs and researchers may enhance the representation of women in psychiatric clinical trials.\u003c/p\u003e","manuscriptTitle":"Inclusion of Women in French Psychiatric Clinical Trials: A Qualitative Study of Researchers’ Experiences and Challenges","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-29 14:49:02","doi":"10.21203/rs.3.rs-6718965/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bfc2fd11-f3de-4ca8-a4c0-4d8be87735c8","owner":[],"postedDate":"June 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T04:08:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-29 14:49:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6718965","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6718965","identity":"rs-6718965","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}