Summary: New research reveals that the developmental timing of fluoxetine (Prozac) treatment profoundly influences long-term mood and brain function. In a rodent model, early postnatal treatment in males led to persistent anxiety and depression-like behaviors, while adolescent treatment reduced these behaviors.
The study also showed opposite effects on neuron structure, gene expression, and brain energy metabolism depending on the treatment window. These findings highlight the importance of timing and sex in antidepressant use during development and suggest possible interventions like vitamin B3 to mitigate adverse effects.
Key Facts:
- Timing Matters: Early-life fluoxetine increased depression-like behaviors, while adolescent treatment reduced them in male rodents.
- Brain Energy Effects: Early treatment lowered prefrontal cortex bioenergetics; adolescent treatment enhanced it.
- Potential Mitigation: Adult vitamin B3 supplementation reversed some negative early-life effects.
Source: Elsevier
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.”
About this psychopharmacology research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is credited to Neuroscience News
Original Research: Open access.
“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” by Vidita A. Vaidya et al. Biological Psychiatry
Abstract
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
Background
Serotonin shapes emotional neurocircuit development, and serotonergic neurotransmission is implicated in both the pathophysiology and treatment of neuropsychiatric disorders. The selective serotonin reuptake inhibitor, fluoxetine (Flx) is a common first-line treatment for childhood and adolescent mood disorders given a favourable risk-benefit profile.
Using a rodent model we addressed specific long-term behavioral, molecular, bioenergetic and cytoarchitectural consequences of postnatal (PNFlx) and juvenile (JFlx) fluoxetine treatment.
Methods
Rat pups received PNFlx (postnatal day 2: P2-P21) or JFlx (P28-48) treatment with the impact on anxiety- and despair-like behavior examined in adulthood, along with assessing global gene expression, mitochondrial function, and dendritic cytoarchitecture in the medial prefrontal cortex (mPFC).
Results
PNFlx and JFlx evoked long-lasting, opposing changes in anxiety- and despair-like behavior in male, but not female, rats. The PNFlx- and JFlx-evoked increase and decrease in anxiety- and despair-like behavior respectively, were accompanied by distinctive, minimally overlapping, transcriptional changes in the mPFC in adulthood.
Furthermore, we noted starkly differing outcomes of PNFlx and JFlx on mitochondrial function and dendritic cytoarchitecture in the mPFC. The PNFlx evoked despair-like behavior was reversed by adult-onset treatment with nicotinamide, a NAD+precursor that enhances mitochondrial bioenergetics.
Conclusions
Collectively, our findings highlight distinct developmental epochs wherein fluoxetine exposure can program long-term, sex-specific, opposing outcomes on mood-related behavior, accompanied by persistent changes in gene expression, mitochondrial function and neuronal cytoarchitecture in the mPFC in adulthood.
This motivates future studies to examine a potential role for altered bioenergetics in shaping the differential impact of early fluoxetine treatment on emotionality.
