Fluoxetine exposure during early auditory development drove 91 gene expression changes in the brainstem, reduced the stability of mature neural circuits, and left lasting hair-cell damage in the inner ear.

Fluoxetine Changed the Developing Auditory Brain and Left the Inner Ear Damaged

Fluoxetine given during the period when hearing connections are still forming damaged the inner ear and destabilized the brainstem circuits that process sound. Researchers at Kyungpook National University found that fluoxetine exposure during this window drove 91 gene expression changes in the brainstem’s first sound-processing relay station, broke down the protective structures that hold mature circuits in place, and shifted molecular activity toward tissue remodeling. The inner ear’s sensory hair cells, the cells responsible for converting sound waves into electrical signals, remained disoriented and lost. Hearing thresholds remained elevated across most frequencies. The findings, published in PLoS One in February 2026, establish that fluoxetine during auditory development produces measurable brain remodeling and lasting sensory damage.¹

The Ear-to-Brain Sound Pathway Is Still Forming After Birth

The nerve fibers that carry sound from the inner ear to the brainstem continue developing after birth. In the model used in this study, these connections reach maturity approximately 2 to 3 weeks after birth. During this formation period, the system is especially vulnerable because the wiring is incomplete. Noise exposure during this time produces lasting hearing damage because the connections the ear depends on for life are still under construction.¹

In humans, the equivalent window spans the early years of life, when the auditory pathway is completing its insulation (myelination), refining its synaptic connections, and organizing its frequency map (the system that allows the brain to distinguish high-pitched sounds from low-pitched sounds). Practitioners managing young patients on fluoxetine are managing patients whose hearing systems may still be in this critical formation period.

Fluoxetine Improved One Frequency and Left the Rest Impaired

All noise-exposed subjects showed elevated hearing thresholds before treatment at 4, 8, 16, and 32 kHz. After 19 days of fluoxetine, the fluoxetine group showed lower thresholds at 4 kHz (a low-frequency tone) compared with the noise-only group. Thresholds at 8 kHz remained unchanged. Thresholds at 16 and 32 kHz remained elevated in every group.¹

The improvement was modest and confined to a single low-frequency point. Hearing remained abnormal overall. Fluoxetine changed molecular signals in the brainstem, and yet actual hearing recovery stayed restricted to one frequency out of four tested.¹

Inner Ear Hair Cells Stayed Damaged Regardless of Fluoxetine

The outer hair cells of the inner ear, the cells that amplify sound before it reaches the brain, were disoriented and lost in all noise-exposed subjects. The fluoxetine group showed the same level of hair-cell damage as the noise-only group. Inner and outer hair cells appeared smaller or shorter in all noise-exposed subjects regardless of fluoxetine treatment. Supporting cells, which maintain the structural environment around hair cells, remained consistent in number across all groups.¹

Two key structural proteins that form protective baskets around inner hair cells, aggrecan (ACAN) and brevican (BCAN), were reduced after noise exposure. These protective markers stayed reduced in the fluoxetine group as well. TrkB, the receptor that binds brain-derived neurotrophic factor (BDNF, a protein critical for nerve cell survival and growth), showed similar levels across all groups in the inner ear.¹

The structures responsible for detecting, amplifying, and transmitting sound stayed injured. The damage to the ear persisted while molecular changes occurred upstream in the brain.¹

Fluoxetine Broke Down the Brainstem’s Mature Circuit Scaffolding

The ventral cochlear nucleus (VCN), the brainstem’s first relay station for incoming sound, showed a pattern distinct from the inner ear. In the fluoxetine group, the protective scaffolding around mature neurons in the VCN, called perineuronal nets, was significantly reduced compared with all other groups.¹

Perineuronal nets are mesh-like structures that wrap around neurons once circuits mature. They lock circuits into stable, efficient configurations. When these nets break down, circuits become more changeable and less stable. The breakdown of perineuronal nets in the VCN means fluoxetine pushed brainstem sound-processing circuits toward instability during a period when those circuits should have been consolidating.¹

BDNF signal increased in fluoxetine-only subjects in the VCN. In the noise plus fluoxetine group, BDNF signal was comparable to the noise-only group and remained at that baseline.¹

91 Gene Changes Confirmed the Brainstem Was Actively Remodeling

Gene sequencing of the VCN identified 39 genes with increased activity and 52 genes with decreased activity in the fluoxetine group compared with the noise-only group. The upregulated genes included Fos, a rapid-response gene that activates when neurons fire, and Adamts4, an enzyme that breaks down extracellular matrix tissue. The overall gene pattern pointed to active tissue remodeling and structural reorganization in the brainstem.¹

Genes involved in neuropeptide signaling, including Adcyap1, Nts, Npy, and Glra1, showed predicted increases. Genes involved in maintaining the cell’s electrical balance (potassium ion homeostasis) and responding to neural activity showed predicted decreases.¹

The gene data confirmed that fluoxetine drove active remodeling in the brainstem at the molecular level. The inner ear stayed damaged. Hearing stayed impaired. The brain was reorganizing its sound-processing circuits while the sensory organ feeding it remained broken.¹

Practical Guidelines

Practitioners prescribing fluoxetine to children and adolescents whose hearing systems are still developing should include baseline and periodic hearing tests as part of ongoing monitoring, because this study demonstrates measurable auditory consequences from fluoxetine exposure during the developmental window.¹

Medication exposure history belongs in every evaluation of hearing complaints or auditory processing symptoms in young patients, alongside noise exposure history, because serotonergic drugs influence how the auditory brain responds to injury.¹

Central brain remodeling and inner ear recovery operate on separate tracks. When a young patient on fluoxetine shows changes in how they process sound, practitioners should evaluate inner ear function directly rather than assuming that brain-level adaptation means the ear is healing.¹

Personalized Medicine

Risk and recovery depend on timing. The postnatal developmental period represents a window of heightened vulnerability that this study anchors as the critical variable. In humans, that window varies by individual based on gestational age, birth timing, and developmental trajectory.¹

Medication exposure and injury timing interact differently across patients. Counseling that accounts for the individual patient’s developmental stage, cumulative noise exposure, duration of fluoxetine use, and any concurrent neuroactive medications provides more accurate guidance than a blanket approach applied across all ages.¹

Holistic Alignment

Timing determines vulnerability. Fluoxetine exposure during auditory development produced lasting structural and molecular consequences that persisted beyond the treatment period. This aligns with prevention-first clinical thinking that prioritizes reducing unnecessary pharmaceutical exposures during critical developmental windows and tracking how medications interact with sensory development over time. Practitioners interested in the broader clinical picture of psychiatric medication exposure during development can find additional context in NDNR’s coverage of the growing demand for psychiatric drug tapering.¹

References

1. An HJ, Choi S, Lee S, Yeo H, Kim SY. Fluoxetine minimally affects hearing loss but induces gene expression changes in the cochlear nuclei after noise exposure. PLoS One. 2026;21(2):e0341746. doi:10.1371/journal.pone.0341746

Further Reading

“The Quiet Surge in Demand for Psychiatric Drug Tapering,” NDNR.com: https://ndnr.com/the-quiet-surge-in-demand-for-psychiatric-drug-tapering/

“The Physiology of Hearing Loss After Loud Sounds,” NDNR.com: https://ndnr.com/naturopathic-news/the-physiology-of-hearing-loss-after-loud-sounds/

“Maintaining Brain Plasticity in Adults: Phagocytosis of Synapses,” NDNR.com: https://ndnr.com/naturopathic-news/maintaining-brain-plasticity-in-adults-phagocytosis-of-synapses/

“Neurodevelopment in Preemies,” NDNR.com: https://ndnr.com/naturopathic-news/neurodevelopment-in-preemies/