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Antidepressant discontinuation during pregnancy and relapse risk in the perinatal period

Periodic Reporting for period 2 - PregnancyAD (Antidepressant discontinuation during pregnancy and relapse risk in the perinatal period)

Période du rapport: 2022-05-01 au 2023-04-30

Antidepressants are commonly used to treat affective disorders, and even pregnant women may receive antidepressants. However, concerns have been raised about the potential effects on the unborn children. As a result, more than half of pregnant women stop taking antidepressants. However, untreated or not adequately treated mental disorders during pregnancy can negatively impact the mother's and child's health. Therefore, expectant mothers face a difficult decision when using antidepressants while balancing their well-being with their unborn children.

Although the effectiveness of psychiatric medications has been established in the general population, there is limited research on the efficacy of antidepressant treatment during pregnancy. Currently, no personalized recommendations are available to determine who can safely reduce or discontinue their antidepressant use without risking a relapse. This lack of guidance makes it crucial from a clinical standpoint to provide evidence-based information to assist in making treatment decisions tailored to individual needs, aiming to minimize unnecessary exposure while maintaining remission.

The main objective of my research, supported by the MSCA fellowship, was to investigate the risk of relapse during the perinatal period following the discontinuation of antidepressants during pregnancy. To achieve this, I conducted several cohort studies by analyzing data from Danish national registers and genetic information. My findings indicate that continuing antidepressant treatment during pregnancy is associated with a reduced risk of relapse and has limited or no adverse effects on unborn children. Women who stop taking antidepressants late in pregnancy face a higher risk of relapse. These findings contribute to the limited evidence available regarding the effectiveness of antidepressant treatment during pregnancy, and they aim to support decision-making regarding antidepressant use in pregnant women.
I conducted several cohort studies to quantitatively assess the risks and benefits of using antidepressants. Overall, my findings suggest that continuing antidepressant treatment reduces the risk of relapse and has limited or no adverse effects on children. Here are the key findings:

1. Individuals on antidepressant treatment for less than 4, 4-6, 7-9, and 10-12 months had cumulative incidences of restarting antidepressants within one year at 37.4%, 35.1%, 35.0%, and 32.8%, respectively. To minimize the risk of relapse after discontinuation, a minimum of 10-12 months of treatment seems preferable.

2. Discontinuing antidepressants during pregnancy increased the risk of psychiatric emergencies compared to continuing treatment (5.0% for discontinuation versus 3.7% for continuation). Approximately for every 76 pregnant women who discontinued antidepressants, there was an additional psychiatric emergency. Continuing antidepressant treatment throughout pregnancy may reduce the risk of psychiatric emergencies.

3. In collaboration with a Norwegian group, we found four similar treatment trajectories. Discontinuing antidepressants early in pregnancy reduced the risk of worsening depressive symptoms postpartum compared to continuers, while discontinuation in late pregnancy increased the probability of increased depressive symptoms. These results were consistent between the two countries.

4. I also examined whether the reduced relapse risk observed among women using antidepressants during pregnancy extended to those with mental disorders other than affective disorders, such as eating disorders and obsessive-compulsive disorders. The beneficial effect was also seen among women who continued antidepressants during pregnancy and postpartum to manage these disorders.

5. The timing of antidepressant discontinuation played a crucial role in relapse risk. Therefore, I conducted a study to examine the determinants of the timing of discontinuing antidepressants. I identified four treatment trajectories: early discontinuers (23%), late discontinuers (24%), interrupters (15%), and continuers(38%). Women who continued or discontinued antidepressants late in pregnancy exhibited more severe mood disorders. However, these differences were not reflected in their polygenic risk scores.

6. Psychiatric disorders that occurred at different timing may indicate distinct severity. I investigated this by employing polygenic scores and found genetic liability to bipolar disorder, but major depression or schizophrenia was associated with a higher risk of postpartum psychiatric disorders that occurred within 30 days after childbirth.

7. To provide a balanced overview of antidepressant treatment efficacy and safety, I also investigated various health outcomes in offspring. I found a slightly increased risk of preterm birth, low birth weight, postnatal adaptation syndrome, neonatal admission, and neonatal persistent pulmonary hypertension among children exposed to antidepressants during pregnancy. However, the relative risks were modest, and the absolute risks were low. Additionally, I found no evidence supporting that maternal genetic liability explains the associations.

I published 12 peer-reviewed papers and have three papers under review. Furthermore, I have disseminated our findings through various channels to reach a wide audience:
1. Conference presentations: I have presented our findings at several important conferences, including the Danish Epidemiological Society Annual Meeting, the NordicEpi, iPSYCH Research Forum Meetings, and the 13th Annual Meeting of the Danish Society for Pharmacology.
2. Press releases and social media engagement: I have issued press releases highlighting our research's key insights and updates. Additionally, I have effectively utilized social media platforms such as Twitter to disseminate our findings.
3. Invited keynote speech: I was invited to deliver a keynote speech at the Aarhus Institute of Advanced Studies (AIAS) conference on June 14, 2022.
4. Presentations at prominent institutes: I presented my research at five renowned institutes, including the Institute for Molecular Bioscience and the Child Health Research Centre at The University of Queensland.
My project has yielded valuable evidence to the limited literature regarding the efficacy of continuing antidepressant treatment during pregnancy in reducing the risk of relapse. Additionally, I have provided a comprehensive assessment of the potential adverse health outcomes in children exposed to antidepressants in utero. I further demonstrated that the relapse risk is mainly determined by the severity of disorders but not the genetic liability to major depression.

These findings have substantial societal significance, as they will inform national guidelines on the use of antidepressants during pregnancy and provide crucial guidance for pregnant women and their physicians when making decisions about treatment options. By offering evidence-based risk-benefit information through counseling, we aim to help women develop more nuanced risk perceptions and make informed choices regarding their mental health care during pregnancy. Additionally, the project's socio-economic impact and wider societal implications lie in the potential to contribute to reducing stigma and improving the understanding of mental health issues during pregnancy, fostering a more supportive and informed society.
Cumulative risk of psychiatric emergency by antidepressant continuation versus discontinuation
Relative risk of initiating psycholeptics by timing of antidepressant discontinuation