Do antidepressants actually alter brain structure? A massive neuroscience study weighs in

A massive brain imaging study has found that subtle differences in the brain structure of people taking antidepressants are largely explained by the severity of their depression, rather than the medications themselves. The research also suggests that the relationship between depression, medication use, and brain anatomy changes across a person’s lifespan, with younger patients showing distinct structural patterns. The findings were published in Molecular Psychiatry.

Major depressive disorder is a severe and persistent form of depression that ranks among the leading causes of disability worldwide. To treat it, doctors frequently prescribe antidepressant medications, yet the exact biological mechanisms by which these drugs alter the brain remain somewhat elusive.

A 2006 theoretical framework proposed that chronic stress and depression might damage brain cells, and that antidepressants could stimulate the growth of new cells in deep brain regions. Supporting this idea, a study covered by PsyPost in 2026 indicated that treatments like duloxetine could help normalize the microscopic structure of brain tissue in depressed patients, whereas those given a placebo saw their brain tissue drift further from healthy levels.

To investigate these effects on a larger scale, researchers needed massive datasets. In prior work, the ENIGMA consortium, an international network of brain researchers, mapped how depression physically alters the brain. For instance, a 2015 study from the group found that people with major depression tend to have a smaller hippocampus, which is a seahorse-shaped structure deep in the brain that plays a primary role in memory and emotion.

Building on this lineage, researchers analyzed data from this same international network to see if antidepressant use actually counteracts these structural brain changes, and whether those effects differ depending on a patient’s age and sex.

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“In several of our previous large international ENIGMA studies of depression, we kept seeing an intriguing pattern: the most widespread brain differences were often found in people with depression who were taking antidepressants at the time of their brain scan,” Lianne Schmaal, head of Mood & Anxiety Disorders Research and chair of the ENIGMA MDD consortium at Orygen and the Centre for Youth Mental Health at The University of Melbourne, told PsyPost.

“We wanted to understand that pattern better,” Schmaal explained. “Our earlier studies did not have sufficiently detailed information about how long people had been taking antidepressants or which type they were taking, and they could not tell us whether the differences we observed were related to the medication itself or to the reasons people were taking medication in the first place.”

To answer these questions, Schmaal, lead author Chaira Serrarens, and their colleagues pooled data from 32 different international cohorts, yielding a total sample of 8,696 individuals. This massive group was divided into three categories: 2,076 people with major depressive disorder who were currently taking antidepressants, 1,495 people with the disorder who were not taking antidepressants, and 5,125 healthy controls with no history of the condition.

“One of the strengths of this study is its scale,” Schmaal said. “By bringing together almost 8,700 people from 32 research cohorts around the world and analyzing their brain scans using harmonized methods, we could identify subtle patterns that smaller studies would struggle to detect reliably.”

All participants underwent structural magnetic resonance imaging (MRI), a technique that uses strong magnetic fields and radio waves to create highly detailed, three-dimensional pictures of brain anatomy. The researchers processed these brain scans using automated software to measure three main things. First, they measured the thickness of the cerebral cortex, which is the wrinkled outer layer of the brain responsible for higher-level thinking and processing. Second, they measured the total surface area of this outer layer. Third, they measured the volume of subcortical structures, which are the specialized hubs located deep beneath the outer cortex.

To ensure a fair comparison, the statistical models accounted for the participants’ age, sex, and total head size. The researchers also gathered clinical data from the depressed patients, including the severity of their current symptoms based on standard psychological questionnaires, their number of past depressive episodes, and, for a smaller subset, the specific type of antidepressant they were taking.

The brain scans revealed a complex relationship between age, medication status, and brain structure. For example, younger individuals in the medicated group (those under 50 years old) showed a thinner middle temporal gyrus compared to both the unmedicated patients and the healthy controls. The middle temporal gyrus is a ridge on the side of the brain involved in processing sensory information and emotional cues. In older individuals, this difference between the groups disappeared, with the lines crossing over around age 50.

“One of the most interesting findings was that age seemed to matter,” Schmaal noted. “Some of the differences associated with antidepressant use were most apparent in younger people and were not seen in the same way in older adults. That suggests we should not necessarily assume that the relationship between antidepressant treatment and the brain is the same across the lifespan.”

When looking at the overall effects of medication regardless of age, the researchers found that patients currently taking antidepressants had a smaller hippocampus and a thinner inferior temporal gyrus compared to patients who were not taking the drugs. The researchers ran extra tests to see if these differences were simply due to the medicated patients having a longer or more stubborn history of depression. The structural differences held true even when adjusting for the number of past depressive episodes or whether the patient was currently in remission.

However, the researchers caution that these alterations are not glaringly obvious on an individual level. “The differences were small,” Schmaal told PsyPost. “They are detectable because we were able to combine data from thousands of people, but they are nowhere near large enough to look at an individual person’s brain scan and determine whether they have taken antidepressants, or to use these measures in clinical decision-making.”

The differences between the medicated and unmedicated groups also vanished when the researchers accounted for the severity of current depressive symptoms. The people in the medicated group generally reported feeling worse at the time of the scan than the unmedicated group. This indicates that the structural differences in the temporal lobe and hippocampus might be tied more to how severely depressed a person is currently feeling, rather than being a direct physical result of the medication itself.

“We tried to account for factors such as current symptoms, number of previous depressive episodes and whether someone had recurrent depression, but it is impossible to completely separate medication use from illness severity in this kind of study,” Schmaal explained.

“Despite exploring every possible difference between those taking and those not taking antidepressants, there were only very small differences in very few brain areas which disappeared when taking into account other important differences between these groups,” Roland Zahn, a professor of Mood Disorders and Cognitive Neuroscience at King’s College London’s Centre for Affective Disorders who was not involved in the research, told PsyPost.

Zahn, who also serves as co-programme lead for the MSc Affective Disorders and shares research updates via his lab blog, added: “One important difference between the groups was that people taking antidepressants had much higher levels of depressive symptoms as measured on a gold standard observer-rated scale known to correlate with subtle changes in brain structure from other studies. When accounting for this crucial difference between the groups, the subtle differences in thickness of some of the brain areas in those taking antidepressants disappeared.”

The study also highlighted brain changes that seem driven by the depression diagnosis itself rather than the medication. Younger patients with depression, regardless of whether they took medication, had a smaller thalamus compared to healthy controls. The thalamus acts as a central relay station for sensory and motor signals in the brain. These younger patients also exhibited a thinner cortex in several regions across the frontal, occipital, and parietal lobes when compared to healthy individuals, a gap that was not present in the older participants.

In a smaller exploratory analysis, the researchers looked at specific types of antidepressants, comparing selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. They found an age-specific pattern here as well. Older adults (over the age of 40) taking mirtazapine had a thicker rostral anterior cingulate cortex compared to older adults taking SSRIs or SNRIs.

This brain region sits in the frontal lobe and is heavily involved in emotional regulation and reward processing. The authors suggest that mirtazapine might trigger a distinct neuroplastic response in this area, though they also note that mirtazapine is often prescribed for specific symptoms like insomnia or after other drugs have failed, which might influence the results.

“The authors acknowledge that they cannot establish causal relationships and particularly their comparison of different antidepressants is exploratory and based on a much smaller group, based on a single time point,” Zahn noted. “The problem is that there are several factors influencing the reason why someone is taking one antidepressant rather than another and the authors acknowledge, they were not able to account for that as this is a large study with limited clinical background information.”

The researchers also investigated how long patients had been on their current medication, finding no clear association between duration of use and structural changes. “We also did not find evidence that a longer duration of current antidepressant use was associated with greater brain differences,” Schmaal said. “That is reassuring in one sense, but it needs to be interpreted cautiously because detailed information on duration was available for only a subset of participants, and importantly we did not have people’s complete lifetime history of antidepressant exposure.”

The findings are in tension with research covered by PsyPost earlier this year, which found that patients taking the antidepressant escitalopram experienced increases in right hippocampal volume during their treatment. Both studies measure hippocampal volume via MRI in depressed patients taking antidepressants, but that earlier study tracked longitudinal within-person volume changes over weeks of treatment, whereas the new study assessed cross-sectional volume differences between different groups of medicated and unmedicated patients at a single point in time.

However, the ENIGMA study’s immense size adds significant weight to its findings. “This is a very important study in that it was able to merge data from thousands of people and therefore had the ability to detect very small differences,” Zahn said. “It thereby challenged findings from non-human animals as well as findings in smaller studies.”

As with all research, there are a few things to keep in mind. The study relies on a cross-sectional design, meaning the participants were only scanned once. Because the researchers did not track the same individuals over time, they cannot definitively say whether the antidepressants caused the observed brain differences, or if people with certain brain shapes and symptom severities are simply more likely to be prescribed antidepressants.

“The main misinterpretation I would want to avoid is that this study shows antidepressants cause the brain to shrink or cause brain damage. It does not,” Schmaal said. “Imagine taking a photograph of two groups of people today: one group taking antidepressants and another group not taking them. Even if their brains differ on average, that photograph cannot tell you what caused the difference or what their brains looked like before treatment.”

Zahn echoed this caution, emphasizing that brain anatomy is highly variable. “It is also important to note that the structure of our brains constantly changes and the biggest driver of such change is age,” he said. “It is also important to note that large individual differences in brain structure exist with little impact on functioning.”

Because of this limitation, the findings should not alter how patients currently manage their condition. “That is why these results should not be used to make decisions about starting or stopping antidepressants,” Schmaal added. “Those decisions need to be based on the balance of benefits and risks for an individual person and discussed with their treating clinician.”

The researchers also lacked data on the participants’ lifetime history of medication use, meaning some people in the “unmedicated” group might have taken antidepressants in the past. Other factors that shape brain anatomy over a lifespan, such as education, lifestyle habits, or early signs of neurodegenerative diseases in older adults, could not be fully accounted for across all 32 international sites.

“The next critical step is longitudinal research,” Schmaal told PsyPost. “Ideally, we need to follow people from before, or very soon after, they first start an antidepressant and repeatedly assess both their mental health and their brain over several years.”

“The next step as the authors acknowledge is to investigate multiple time points in datasets which contain more detail about other relevant factors, such as other conditions, and response to previous treatments,” Zahn added.

“Ultimately, the goal is not simply to ask whether antidepressants affect the brain,” Schmaal concluded. “We want to understand how they affect the developing and adult brain, whether those effects differ between individuals and across different ages, and whether any brain changes relate to treatment benefit, side effects or longer-term outcomes.”

The study, “Regional brain morphology and current antidepressant use: findings from 32 international cohorts from the ENIGMA major depressive disorder working group,” was authored by Chaira Serrarens, Yara J. Toenders, Elena Pozzi, André Aleman, Nina Alexander, Zeynep Başgöze, Vladimir Belov, Klaus Berger, Katharina Brosch, Robin Bülow, Geraldo Filho Busatto, Liliana P. Capitão, Colm G. Connolly, Baptiste Couvy-Duchesne, Kathryn R. Cullen, Udo Dannlowski, Christopher G. Davey, Greig I. de Zubicaray, Danai Dima, Katharina Dohm, Verena Enneking, Tracy Erwin-Grabner, Ulrika Evermann, Cynthia H. Y. Fu, Paola Fuentes-Claramonte, Beata R. Godlewska, Ali Saffet Gonul, Ian H. Gotlib, Roberto Goya-Maldonado, Hans J. Grabe, Nynke A. Groenewold, Dominik Grotegerd, Oliver Gruber, Tim Hahn, Geoffrey Hall, Ben J. Harrison, Walter Heindel, Marco Hermesdorf, Tiffany C. Ho, Naho Ichikawa, Eri Itai, Neda Jahanshad, Hamidreza Jamalabadi, Alec J. Jamieson, Andreas Jansen, Tilo Kircher, Bonnie Klimes-Dougan, Bernd Krämer, Axel Krug, Thomas M. Lancaster, Elisabeth J. Leehr, Meng Li, David E. J. Linden, Frank MacMaster, Katie L. McMahon, Sarah E. Medland, David M. A. Mehler, Susanne Meinert, Benson Mwangi, Igor Nenadić, Go Okada, Yasumasa Okamoto, Nils Opel, Julia-Katharina Pfarr, Edith Pomarol-Clotet, Maria J. Portella, Ronny Redlich, Liesbeth Reneman, Jonathan Repple, Kai Ringwald, Elena Rodriguez-Cano, Pedro G. P. Rosa, Matthew D. Sacchet, Philipp G. Sämann, Raymond Salvador, Anouk Schrantee, Hotaka Shinzato, Kang Sim, Egle Simulionyte, Jair C. Soares, Dan J. Stein, Frederike Stein, Benjamin Straube, Lachlan T. Strike, Florian Thomas-Odenthal, Sophia I. Thomopoulos, Paul M. Thompson, Marie-Jose van Tol, Paula Usemann, Aslihan Uyar, Nic van der Wee, Steven van der Werff, Yolanda Vives-Gilabert, Henry Völzke, Martin Walter, Sarah Whittle, Katharina Wittfeld, Adrian Wroblewski, Mon-Ju Wu, Tony T. Yang, Giovana B. Zunta-Soares, Dick J. Veltman, Lianne Schmaal, and Laura S. van Velzen.