Common antidepressant may increase pain sensitivity later in life if taken during adolescence

A new study published in the Journal of Psychiatric Research raises concerns about the long-term effects of fluoxetine—better known by its brand name Prozac—when used during adolescence. Researchers found that female mice given fluoxetine during a juvenile period displayed heightened sensitivity to pain and lower body weight in adulthood, even weeks after treatment had ended. The findings suggest that adolescent exposure to this commonly prescribed antidepressant may have lasting effects beyond mood regulation.

Fluoxetine is a selective serotonin reuptake inhibitor widely used to treat depression, anxiety, and premenstrual disorders, especially in adolescents. Prescription rates for fluoxetine have been rising sharply among young people, particularly girls. The increase has been partly attributed to growing mental health needs during and after the COVID-19 pandemic, during which in-person therapy was less available.

Previous research has shown that early-life exposure to fluoxetine can lead to lasting changes in mood, memory, and drug sensitivity. These behavioral effects are often linked to changes in brain circuits involved in emotion regulation, such as the prefrontal cortex and amygdala. Some studies have also suggested that fluoxetine can affect inflammatory processes and body weight, raising the question of whether its effects extend into other areas, such as pain perception.

“Our lab has been interested in this topic due to growing concerns about the increased use of antidepressants like Prozac (fluoxetine) among young girls. Since adolescence is a crucial period of development, the idea that medications affecting neurotransmitter systems, like serotonin, may have long-term consequences on brain function and behavior, including pain sensitivity, is particularly alarming,” said study author Sergio Iñiguez, a professor of psychology at the University of Texas at El Paso.

The researchers conducted a controlled experiment using female C57BL/6 mice, a widely used laboratory strain known for its genetic consistency and well-documented behavioral and physiological responses. Twenty adolescent mice were randomly divided into two groups. One group received fluoxetine dissolved in their drinking water for 15 days during adolescence—starting on postnatal day 35 and ending on day 49. The other group received regular water and served as a control. The dosage of fluoxetine was designed to match levels known to have antidepressant-like effects in rodents, adjusted for the higher metabolic rates found in females and younger animals.

Three weeks after the treatment period ended—when the mice had reached adulthood at postnatal day 70—the researchers assessed the animals’ sensitivity to thermal pain using the hot plate test. This test involves placing a mouse on a heated surface and measuring the time it takes for the mouse to show a pain response, such as licking its hind paw. Shorter reaction times suggest increased sensitivity to pain, a condition known as hyperalgesia.

The researchers found that mice exposed to fluoxetine during adolescence responded to the heat stimulus significantly faster than those in the control group. On average, they took less time to lick their hind paw, indicating that they were more sensitive to pain. Importantly, this increased sensitivity was observed well after the drug had been cleared from their system, suggesting a lasting change in their pain-processing mechanisms.

The researchers also tracked body weight throughout the experiment. Mice that received fluoxetine began to gain less weight starting on the second day of treatment, and this effect persisted into adulthood. At the time of the pain sensitivity test, the fluoxetine-exposed mice weighed significantly less than the controls. Although reduced body weight might influence pain responses, previous work suggests that fluoxetine does not impair general movement in rodents, making it unlikely that changes in locomotion affected the test results.

“Adolescent exposure to antidepressants like Prozac may have long-lasting effects that extend beyond mood regulation and can influence sensory processes, such as pain sensitivity,” Iñiguez told PsyPost. “Increased pain sensitivity in adulthood could be an unintended consequence of SSRIs, which is especially important to consider when prescribing these medications to young people.”

These findings align with earlier studies showing that early-life fluoxetine exposure can cause long-term alterations in brain function. In particular, serotonin—the chemical targeted by fluoxetine—plays a key role not only in mood but also in the regulation of pain. Disrupting serotonin levels during adolescence may interfere with the normal development of brain regions involved in processing pain, such as the prefrontal cortex. This area continues to mature during the teenage years and is involved in both emotional regulation and pain perception.

Other studies have shown that fluoxetine can affect inflammation, another pathway that influences how pain is experienced. For instance, clinical research has found that children and adolescents treated with fluoxetine show elevated levels of inflammatory markers like interleukin-6 and interleukin-1β months after treatment. This kind of immune activity could sensitize pain pathways and lead to lasting changes in how the brain and body respond to discomfort.

While the results of this study are based on an animal model and should not be directly applied to humans without further research, they raise important questions about how antidepressants may influence more than just mood. In particular, they suggest that fluoxetine use during adolescence could carry unintended consequences for sensory processing in adulthood.

One limitation of the study is that it did not include additional stressors, which are often present in human experiences of depression and anxiety. Stress is known to interact with both mood disorders and pain perception, and it is possible that the combination of fluoxetine and environmental stress would lead to different outcomes. Future research should examine how fluoxetine interacts with stress and other common adolescent experiences, including the use of other medications or the presence of psychiatric symptoms.

Another point to consider is that fluoxetine is prescribed for a range of conditions beyond depression, including eating disorders and premenstrual mood symptoms, both of which are more common in adolescent girls. Since these conditions themselves may involve altered sensitivity to pain or changes in body weight, more studies are needed to tease apart the effects of the medication from the effects of the underlying disorder.

“We plan to evaluate molecular markers within brain circuits involved in pain processing, particularly focusing on regions such as the prefrontal cortex and hypothalamus,” Iñiguez said. “We hope that the findings of this project inspire other researchers to further investigate the potential long-term side effects of SSRIs in adolescents, especially considering that antidepressants are frequently prescribed during this stage of development for a variety of illnesses.”

The study, “Prozac exposure during adolescence increases pain sensitivity in adulthood,” was authored by Anapaula Themann, Minerva Rodriguez, Daniel E. Calvo, Paulina Vargas, and Sergio D. Iñiguez.