Treatment timing is critical to Prozac’s impact on mood behaviors

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 published in Biological Psychiatry 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, Ph.D., 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, Ph.D., 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.”

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 published in Biological Psychiatry 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, Ph.D., 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, Ph.D., 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.”