Treatment timing is critical to Prozac's impact on mood behaviors
Findings published in Biological Psychiatry can guide informed choices in the treatment of children and adolescents with depression
Elsevier
image:
Findings from a study in Biological Psychiatry show that the timing of treatment critically shapes Prozac's impact on mood and brain behaviors, helping to guide informed choices in the treatment of depression from childhood through adolescence.
view moreCredit: Biological Psychiatry / Ghai et al.
Philadelphia, July 7, 2025 – Researchers have found that the timing of when fluoxetine (commonly known by its brand name, Prozac) is administered is vital in determining the impact it has on long-lasting mood behavior and accompanying changes in the prefrontal cortex. The new study in Biological Psychiatry, published by Elsevier, provides crucial mechanistic insights into alterations in neurocircuits that regulate mood behavior, which are key to making informed choices in treating depression in children and adolescents.
Serotonin, the neurotransmitter that is modulated by selective serotonin reuptake inhibitors (SSRIs) like Prozac, is known to have a critical impact on neurodevelopment, influencing the fine-tuning and maturation of emotional neurocircuits. Due to its perceived favorable risk-benefit profile, Prozac is often the drug of choice for gestational and postpartum depression in mothers and treating childhood and adolescent depression.
Lead investigator Vidita A. Vaidya, PhD, Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India, explains “Using a rodent model, we addressed specific long-term behavioral, molecular, bioenergetic, and cytoarchitectural consequences of postnatal and juvenile fluoxetine treatment. We found that treatment with fluoxetine during early postnatal life in male, but not female rats, led to long-lasting increases in anxiety- and depression-like behaviors, whereas treatment during adolescence had the opposite effect, significantly reducing these behaviors. This was noted as long as six months after the cessation of drug treatment, highlighting that modulation of serotonin levels with SSRIs like Prozac in developmental windows can result in behavioral changes that are highly persistent.”
Co-investigator Utkarsha Ghai, PhD, Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India, adds, “The diametrically opposing influence of early postnatal and adolescence fluoxetine treatment on mood behavior was also noted in the completely different influence on gene expression, architecture of neurons, and bioenergetics (the brain’s energy levels) in the prefrontal cortex. While early postnatal fluoxetine resulted in a long-lasting decline in bioenergetic status in the prefrontal cortex, adolescent exposure increased bioenergetics, uncovering a previously unknown role for fluoxetine administration in specific developmental windows."
The researchers point out that the impact on neuronal bioenergetics is likely critical, as the long-lasting increase in depressive behavioral responses noted with early postnatal fluoxetine treatment could be reversed by adult-onset nicotinamide (vitamin B3), a NAD+ precursor that enhances mitochondrial bioenergetics treatment.
John Krystal, MD, Editor of Biological Psychiatry, comments, "The notion that antidepressant effects may differ by sex and at different stages of development could be clinically important. It is interesting that the stark biological differences between fluoxetine effect among early postnatal and juveniles are limited to males. As we come to understand the human correlates of the changes observed here in rodents, it may become important to be able to prevent these effects. Thus, the finding that vitamin B3 (nicotinamide), which could easily be administered to boys exposed to fluoxetine, seems to prevent the metabolic and structural consequences of fluoxetine exposure in male rodents.”
Dr. Vaidya concludes, “The novelty of this research lies in the discovery of more than one sensitive window during postnatal life, during which perturbing serotonergic neurotransmission via fluoxetine can exert completely differing effects on mood behavior. While it is difficult to directly extrapolate the time windows in our studies with rodents to the exact equivalent human age, our results underscore the importance of considering both the temporal window of treatment and sex as key variables that can influence the molecular, cellular, bioenergetic, and behavioral outcomes of exposure to fluoxetine during vulnerable developmental stages. We believe this work may motivate further studies to carefully examine the influence of disruption of serotonin signaling in sensitive developmental epochs in both animal models and in clinical cohorts on mood behavior.”
Journal
Biological Psychiatry
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Postnatal and juvenile fluoxetine treatment evokes sex-specific, opposing effects on mood-related behavior, gene expression, mitochondrial function, and dendritic architecture in the rat medial prefrontal cortex
COI Statement
The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article. John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available at https://www.biologicalpsychiatryjournal.com/content/bps-editorial-disclosures.
The Estonian Biobank data helps explain why some individuals experience more side effects from antidepressants
Estonian Research Council
image:
Study´s author: Hanna Maria Kariis. Photo by Karl Erik Piirimees.
view moreCredit: Photo by Karl Erik Piirimees.
Researchers at the University of Tartu Institute of Genomics have gained a deeper understanding of why some people are more prone to experiencing side effects when taking antidepressants.
Analysing data from over 13,000 gene donors who had used antidepressants, the team studied 25 common side effects across 16 frequently prescribed antidepressants in Estonia, such as nausea, weight gain, sleepiness, headaches, and heart palpitations. The study was published in the European Journal of Human Genetics.
According to the study’s author, Hanna Maria Kariis, the focus was on the CYP2C19 gene, which, together with other factors, affects how quickly the body can metabolise certain antidepressants. “Understanding the basic genetic mechanisms underlying side effects helps identify people who belong to a risk group for developing side effects, which can improve treatment outcomes,” said Kariis, highlighting the significance of the study.
It was found that, compared to normal metabolizers, slow metabolizers (people with a genetic variant causing the medication to break down more slowly in the body) were 49% more likely to experience side effects. In comparison, ultra-rapid metabolizers had a 17% lower likelihood. “This means that the same medication may affect individuals very differently depending on their genetic profile, and depending on how quickly the drug is metabolised, a doctor may recommend a dosage adjustment or the use of a different antidepressant,” explained Kariis. All gene donors can check their CYP2C19 gene activity on the Minu Geenivaramu (“My Genome”) portal.
For the first time, the study also analysed a CYP2C19 deletion found in over 3% of Estonians, where a large portion of the gene is missing. “This mutation has not been described in other populations before, so its effects on people have not been studied. It is an important discovery for Estonia,” Kariis noted. The results revealed that the deletion strongly impacted the development of side effects, and the genetic variant should therefore be added to the pharmacogenetic tests available in Estonia. “By doing so, we could reduce the risk of side effects among people in Estonia who take antidepressants,” Kariis added.
Researchers further explored whether genetic predispositions to psychiatric disorders influence side effect occurrence. Genetic predisposition for schizophrenia or depression was associated with more side effects across multiple antidepressant classes. Likewise, individuals with a genetic predisposition for higher BMI were more likely to experience weight gain from antidepressants.
A meta-analysis comparing the results with an Australian study confirmed strong links between polygenic risk for higher BMI and antidepressant-induced weight gain. People with a genetic predisposition to headaches also reported more headaches when taking sertraline-based drugs.
To arrive at these conclusions, the scientists used anonymised responses from mental health and adverse effects questionnaires as well as medical records, employing data mining and natural language processing (NLP) methods to detect mentions of side effects in clinical notes.
The study underscores the potential of genetic data to personalise antidepressant treatment, improving treatment outcomes and minimising therapy discontinuation due to adverse effects.
Read more: https://www.nature.com/articles/s41431-025-01894-x.
Journal
European Journal of Human Genetics
Method of Research
Meta-analysis
Subject of Research
People
Article Title
Genetic influences on antidepressant side effects: a CYP2C19 gene variation and polygenic risk study in the Estonian Biobank
No comments:
Post a Comment