Antidepressants affect male brains, but do little to female brains: Study

Hindustan Times

03-07-2025

Antidepressants have strong impact on male brains — with the nature of the impact depending on the age of the subject — but do not affect female brains, a new study of rats has shown, suggesting that there needs to be more exploration of the physiological effects of such drugs, something that could eventually influence how they are used in treatments. Selective serotonin reuptake inhibitors (SSRIs) are the most prominent intervention for depression, anxiety, and other neuropsychiatric disorders, and allow for more serotonin in the brain as a result. (Representational image)
The neurohormone serotonin plays a large role in shaping emotional pathways in the brain, because of which its regulation is a common target of antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are the most prominent intervention for depression, anxiety, and other neuropsychiatric disorders, and allow for more serotonin in the brain as a result.
Fluoxetine — commonly known by brand names like Prozac, Fludac, and Sarafem — is the most widely used SSRI for all ages, including for pregnant women, lactating mothers, children and adolescents. The study examines the long-term effects of fluoxetine in rat brains when administered at a young age, lead to a series of findings that raise more questions than answers.
Early administration of the drug led to long-term but wildly opposing changes in male brains — when administered just after birth, the rats became more anxious over time; when administered during the juvenile window when they reach sexual maturity, they developed less anxious and depressive behaviours. Additionally, the researchers also observed changes in neuron structure in the brain, changes to energy production by mitochondria, and gene expressions or activation of a group of genes. Most surprisingly, only male rats were affected by the drug. Female rats that were given the drug at the same time windows displayed no long-term changes in behaviours, brain structure, mitochondria, or genetic expressions.
'Fluoxetine is the most common drug given to individuals under the age of 18, as well as to pregnant women because of its good risk-benefit profile, but people have not yet worked on these specific windows of administration in a systematic way to evaluate long-term effects,' explained Utkarsha Ghai, lead author of the paper who finished her PhD at TIFR-Mumbai and is a postdoc at NIMHANS Bengaluru. 'Our findings prove the window of administration of these antidepressants and the gender of the person, all these variables actually matter.' The findings were published in the Biological Psychiatry journal.
What the study showed
The primary findings of the study show that the age at which antidepressants are given affects their effects, sometimes exacerbating depressive tendencies and resulting in the opposite of what they're supposed to do.
The team of TIFR scientists set out to examine the effects of fluoxetine on the brain before and after sexual hormones become active, dividing their young rats into two groups – the post-natal group consisted of rats that were 2-21 days old, while the juvenile group were 28-48 days of age. In humans, these findings translate to similar but significant time windows of age—post-natal equivalent is paediatric, from the third trimester to a few years of age until sexual hormones appear; and juvenile would refer to the age of beginning of sexual hormones (typically teenage years) until the complete development of the pre-frontal cortex in the brains, or adolescence up to the age of 25.
'We have known for a while that serotonin levels play a huge role in shaping emotional circuitry in the long term, especially when they are fiddled around with in a developing brain,' said Vidita Vaidya, principal investigator of the study and professor of neurobiology at TIFR. 'Because SSRIs pass through the placental barrier in pregnant women and enter foetal brains, as well as being transmitted through breastmilk there is ample clinical data indicating that we need to look at these age-related effects more closely.'
Behavioural effects were noticed right away with the rats when they reached adulthood (3 to 6 months of age). The juvenile administered group showed increased resilience and curiosity, explored their test settings more and exhibited less despair and anxiety behaviours. But the rats that were given the drug in babyhood, the post-natal group, showed drastically increased despair and anxiety as adults.
'We saw very long-lasting effects, observed up to 18 months in these rats,' explained Vaidya (rats live for about 24 months). 'Such strong behavioural changes immediately imply there is likely perturbation associated with transmission of signals in the brains, and possibly in the architecture of neurons'.
Indeed, the authors found that in the post-natal group, there was a strong atrophy and physical degradation of neurons or nerve cells in the brain that transmit signals, with the exact opposite effect in the juvenile group. When they examined changes in genetic expressions or identifying which sets of genes were affected, they noticed distinct changes in two groups—those associated with synaptic architecture that has to do with neurons firing in the brain, and those associated with mitochondrial regulation. Mitochondria, fondly known as the powerhouse of the cell, was also strongly affected in opposite ways in the experiment. For the post-natal group, it was again affected adversely, with its ability to produce energy and the total energy produced, both reduced. This reduced bioenergy production resulted in both reduced physical metabolism and lowered energy for neurons to fire in the brain. For the juvenile group, both were boosted. There were close to 500 genes each for both groups that were dysregulated, resulting in upregulation (increased production of gene products like proteins) and downregulation, but it appears that a mere four genes are common between both sets. Affected genes included those involved in metabolism and immune responses. 'The results are mind-blowing,' said Ghai. 'The entire process kept us on our toes, especially when we found such stark differences in a downstream molecular pathways that needed to be explained.'
Male brains can reverse, but female brains completely unaffected
Such long-lasting and adverse changes due to early exposure to SSRIs on the brain would need treatment and potential reversals, so the team also studied the effects of nicotinamide or vitamin B3—known to boost mitochondrial function—when administered to these rats as adults.
Surprisingly, they found several of the adverse effects observed in post-natal rats were reversed completely, with their metabolism restored and a drastic reduction in their despair behaviours.
The other most significant finding from the study was that all of the effects described seemed to appear only in adult male rats. Female rat brains were entirely spared of any effect into adulthood. 'We saw similar changes immediately after administration for both males and females in the early window, but for female rats, the effects were not long-lasting. By the time they reached adulthood, none of the effects persisted. It seems females are entirely spared,' said Ghai.
Potential reasons for this could be future protection accorded by estrogen and other female hormones, or genetic differences from sex chromosomes, or other reasons, requiring further study.
'The sex-selective effect is a big surprise,' said Biju Vishwanath, Additional Professor of Psychiatry at NIMHANS, unaffiliated with the study. 'There is no difference between men and women in therapeutic effects when it comes to antidepressants, so these findings are significant. But mainly what stands out is the difference in the two age windows. In practice, we administer these drugs to patients as young as 5 or 6 years who are depressive. So seeing that it results in these kind of functional changes is important for clinicians.'
He also added that the ability to reverse these effects with vitamin B3 are a key finding.
'As a psychiatrist, these studies are crucial for us to be able to prove and validate that these drugs lead to physiological changes in brain and mitochondrial function, and this has a huge impact on practice.' Vaidya also noted that when some post-natal group rats were given fluoxetine in the juvenile window, their effects neutralised — they had neither better nor worse effects, indicating the importance of age of intervention with antidepressants.
'If a pregnant woman is suicidal or a new mother has post-partum depression, they still need to be treated with SSRIs. But these pass to the child through both the placenta and breast milk,' said Vaidya. 'This could potentially induce or worsen suicidal ideation in those children as they enter adulthood. Timely interventions such as with Vitamin B3 are helpful to treat adverse effects even later in life.'
Sandhya Ramesh is a Bengaluru-based science journalist and writer.