Developmental Fluoxetine Exposure Affects Offspring Anxiety-Like Behavior and Hormonal Response to an Acute Stressor

April 2, 2021   /  

Student Name: Bryce Knopp
Major(s): Biology
Advisor(s): Dr. Lynn

Most Creative Slideshow Award (Honorable Mention)

A large number of women who suffer from depression during pregnancy and the postpartum period are prescribed selective serotonin reuptake inhibitors such as Fluoxetine (Prozac). However, due to Fluoxetine’s ability to cross the placenta and be excreted into milk, maternal treatment with this drug may expose the fetus/offspring to therapeutic levels of Fluoxetine and its metabolites. Physical and behavioral alterations have been reported in offspring exposed to elevated levels of Fluoxetine during early development. Thus, the aim of this study was to determine if Fluoxetine exposure during (1) pregnancy and lactation or (2) only during lactation, affects offspring behavior and physiology. To do this, three groups of Sprague-Dawley rat dams were treated with Fluoxetine (5 mg/kg/day) during pregnancy and throughout lactation, during lactation only, or with regular water. Behavioral testing to examine anxiety-related behaviors of offspring (PND 25-26) was observed on the elevated plus maze and novelty-suppressed feeding test. Blood draws for hormonal analysis were conducted within 48 hours following behavioral testing. Results showed that developmental exposure to Fluoxetine had nuanced effects on anxiety-like behavior in the elevated plus maze but not in the novelty-suppressed feeding test. Data also showed that developmental Fluoxetine exposure decreased serum corticosterone level in response to a stressor in both treatment groups compared to the control. Taken together, these data suggest SSRIs affect the developing HPA system. Given the increasing use of SSRI medication to treat maternal mood disorders, there is need for a more comprehensive understanding of how these medications influence offspring growth and development during specific points of early development.

Bryce will be online to field comments on April 16: 4-6 pm EDT (PST 1pm-3pm, Africa/Europe: late evening)

55 thoughts on “Developmental Fluoxetine Exposure Affects Offspring Anxiety-Like Behavior and Hormonal Response to an Acute Stressor”

  1. Thanks for sharing this work Bryce. Now that you’ve looked at both elevated plus and novelty suppressed feeding behaviors (and not necessarily from your data, but your actual experience), do you have a sense of one being a “better” measure of anxiety-like behaviors in rodents?

    1. Hi Dr. Stavnezer,

      Thank you for your question! I think it’s difficult to say whether one measure is “better” than than the other since they both have unique benefits. I think the elevated plus maze was good because of how well established it is in the literature, whereas the novelty-suppressed feeding test was a good tool to distinguish between acute and chronic effects of antidepressants.

      In general, they both were easy to carry out and provided important insights. I enjoyed using both of these behavioral tests!

  2. Great work Bryce! This was a very interesting presentation. Since your work highlights a disparity in the hormonal response of the rodents in the treatment and control group, are there alternatives people can use in place of SSRIs? Also, do think these effects will persist over a long period of time (perhaps indefinitely) or might the rodent “normalize” over time?

    Again, great job and thank you for sharing this work!

    1. Hi Drew,

      That’s a great question! Right now the potential risks of SSRI use don’t outweigh the known benefits so it’s hard to say whether there are any viable alternatives with equivalent benefits at the moment.

      In the reading I have done, it seems that adolescent rodents were more affected by Fluoxetine exposure, however, there’s some evidence of alterations persisting into adulthood. In general though, behavioral data seems to be all over the place with some research articles reporting no observed alterations at all. My study looked at the effects of fluoxetine on pre-adolescent rodents, so it’s possible/likely that age played a role in my study.

  3. Very interesting study. Do all drugs that cross the BBB also cross the placenta? Would some anti-depressives be safe to use during pregancy?

    1. Hi Kevin,

      Thanks for your questions! The first question is sort of out of my expertise since I only looked at fluoxetine, but characteristics of the drug, such as lipid solubility, can affect whether a drug can cross the blood brain barrier and/or the placenta. Right now, there’s not enough evidence to prevent women from taking an SSRI like fluoxetine since it is effective in treating postpartum depression symptoms.

  4. Great project and great findings. Also, I really enjoyed and appreciated your presentation, as it was easy to follow and understand the results. Congratulations!

  5. Thank you for sharing your findings on this important topic! What did you find most exciting about this project?

    Congratulations, Bryce!

    1. Hi Dr. Mamtora,

      Thank you so much! I really liked working with the rats, they were really cute, especially when they were young! I was also excited to see my hormonal results, I thought it was so interesting to see significant results.

  6. BRYCE 👏BRYCE 👏BRYCE 👏BRYCEBRYCEBRYCE 👏 Congrats on all your hard work! I love your presentation. Also, such an important and relevant area of research in maternal health. Given the significance of your results, what do you think are some of the harmful long-term implications of the drug in terms of the development of treated offspring?

    1. TESS TESS TESS! Thank you so much! Given my results, it seems that the offspring exposed to treatment had an impaired hormonal response to a stressor. Having an effective stress response is super important for your health, so I wouldn’t be too surprised if they have long-term health problems. However, I only examined pre-adolescent offspring so it’s hard to say whether my observations are those that will persist into adulthood.

  7. Very interesting! And just an excellent job with the presentation. Congratulations on your IS and your graduation.

  8. Great job Bryce! Your presentation was super easy to follow and understand. Since rats are used as a model organism in biology, how well would these results translate to humans?

    1. Hi Julia,

      Thanks! Rats are a well studied model organism for human research and are relatively similar in terms of anatomy, physiology, and genes. They are not a perfect match, but are close enough to draw comparisons.

  9. Great work Bryce! As a scientist/health care worker myself, I’m always interested in learning. Your experiment is a great example of process and design. It brings me back when I completed my own Individualized Study at Gettysburg College looking at the effect of different salt concentrations in food in drosophila development.

    A few questions for you:
    -> How was the experimental dose of Fluoxetine in these SD rats determined? Is there a standard dose already published or was a previous dose escalation experiment to determine a therapeutic dose completed?
    -> Would a higher N of the study arms increase your probability of success (PTS) in your experiment?
    -> Are you planning to pursue a graduate degree?

    Congratulations again on your work!

    1. Hi Scott,

      Thank you so much! Your experiment sounds really interesting, I’d love to hear more about it!

      I determined my experimental dose from previous literature. 5 mg/kg seemed like a good route to go because there have been observable behavioral changes and small chance of impact on litter viability at this amount.

      I’m really sorry, I’m not sure what you mean in this question. If you can, do you think you can elaborate?

      Yes! I’m planning on taking a gap year, and then working towards my master’s and eventually becoming a physician assistant!

      1. My second question is related to the sample size. If you had a larger sample size of rats, do you think you may have been able to see a statistical difference given the statistics?

        1. Ah I see! It’s hard to be certain but I imagine that I would continue to see a statistically significant trend in the hormonal section, especially since the data I observed are similar to those in several other studies. In the behavioral tests, I’m not a sure since the behavior responses which have been previously reported are so diverse. I think it would be really interesting to look into!

      2. Oh and btw (forgot to mention), I’m a Family Nurse Practitioner but now work in Medical Affairs at a Biotech company as a Senior Field Medical Director in Hematology!

  10. Awesome presentation, Bryce!
    How do you think anti-anxiety medications or antidepressants other than fluoxetine would affect the results?

    1. Thanks Nicole!

      It’s hard to say whether other anti-anxiety/antidepressant would have similar or different results. I think it would be really interesting to run a similar experiment with a different medication.

  11. Great job Bryce!! This presentation is great (and very non-STEM friendly). Do you think you would get similar results if you repeated the experiment with an SNRI? Why or why not?

    1. Thanks Kath!

      SNRIs are sort of similar to SSRIs in that they can be transferred across the placenta and also into breastmilk. I’m not 100% certain that I would get similar results with an SNRI but I think it is something that would be really interesting to pursue.

  12. Amazing job, Bryce! This is certainly fascinating and important research. I really appreciate how accessible your presentation was, even for a non-STEM major like myself! Thank you for sharing your work and congratulations!

  13. Congratulations Bryce!! Such an interesting topic and amazing work!! Proud of you!!

  14. Such an interesting and important line of study, given the prevalence of SSRIs in our society.
    Well done and congratulations on your research and award.

  15. Such an interesting project! How do you think Prozac would affect offspring if the mothers took it throughout all of their gestation? Also, do you think your results would differ if you used an anxiety-strain of rats instead of the SD ones?

    1. Thanks Maggie! From the reading I did, it seems like offspring seem to be more affected by fluoxetine if a mother is taking it throughout pregnancy/ a longer period of time. I’m not certain about your second question, I didn’t read about any studies which used a genetically modified anxiety-strain of rat but I think that would be really interesting!

  16. Awesome job Bryce! It is super interesting that stress hormones of rats were decreased in both treatment groups, but one treatment group experienced anxiety-like behaviors in the elevated-plus maze. Is there a potential reasoning behind that?

    1. Thanks Lydia!

      Hormones do cause behaviors so it’s not super surprising that the hormonal and behavioral responses don’t match up!

  17. This is so amazing, Bryce! I’m so excited to see all your hard work and research all come together. If you could do this study again with no limits, what would you change?

    1. Thank you Bailey! If I could do this again, I think I would add an additional treatment group where rodent mothers are only treated during pregnancy. I’m super curious about how the timing and duration of treatment affects the offspring!

  18. Excellent work. And it was my privilege to announce your Honorable Mention during the awards presentation. Congratulations!

  19. Congrats Bryce! This is so interesting, and very important as so many women take anti-depressants during pregnancy. You made this super easy to understand.

  20. Great presentation Bryce! It was very engaging and easy to understand. What was it like working with rats? Would you work with them again in the future?

    1. Thanks Erica! The rats were really cool, I would definitely work with them again in the future!

  21. Congratulations, Bryce! This is a fascinating and well-executed study. I have two main questions:
    1) How did you choose the behavioral tests you used? Are there other tests you’d want to apply, if you were to run a similar study again?
    2) Relatedly, do you want to continue down this specific path of research? If so, what questions would you want to answer in future studies?
    Congratulations again!

    1. Thank you Z! I chose my behavioral tests based on previous literature and how well established they are. I don’t think I’d add any other tests since it could affect how the offspring behave, but if I could start fresh, I would consider using the open field test and maybe the elevated zero maze if it were available. I would totally be interested in pursuing this research if I could. I’d be interested in examining how duration of exposure affects the offspring.

  22. Hello Bryce, and congratulations on doing this excellent work! It’s great to catch up with you now, as I think all the way back to FYS. Thank you for presenting your work here today, so that others can benefit from it. I’ll say what Dante wrote above — your presentation is super-clear and accessible to a non-STEM audience, so thanks for doing such a great job! 🙂

    1. Hi Dr. Graham,

      Thank you, I really appreciate it. Thank you for all of your advice over the years! You’re the best!

  23. Fantastic job, Bryce! This is such an interesting and valuable topic! Could you elaborate on what it means for the rats exposed to fluoxetine to have a dampened hormonal stress response?

    1. Thank you Casey! By dampened hormonal response, I meant that the change between the base-line level and the following “stress-out” level of stress hormones in the treatment group offspring was less than that of the control group!

  24. Hi Bryce,
    I was involved with the launch of Zoloft (sertraline) many years ago, so I found the topic of your thesis and the arguments you develop very thought provoking. Thank you for sharing, and congratulations!

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