Antipsychotics cause reversible structural brain changes, study finds

A neuroimaging study conducted in the United Kingdom found that taking the antipsychotic amisulpride (400 mg/day) for one week increased the volume of the left putamen and right caudate regions of the brain. Similarly, taking aripiprazole (10 mg/day) for the same period increased the volume of the right putamen. These changes reversed within weeks after participants stopped taking the medications. The paper was published in Neuropsychopharmacology.

Antipsychotics are a class of psychiatric medications primarily used to manage psychotic disorders such as schizophrenia, schizoaffective disorder, and sometimes bipolar disorder. They work by altering the activity of neurotransmitters in the brain, especially dopamine, which plays a key role in thought, mood, and perception. Currently, blocking dopamine-mediated neural transmission is the standard approach in the pharmacological treatment of psychotic disorders. Most antipsychotics achieve this by blocking dopamine D₂ receptors, which helps reduce hallucinations, delusions, and disorganized thinking.

Neuroimaging studies have consistently shown that certain brain regions differ in volume in people with psychotic disorders. However, these individuals are also typically taking antipsychotic medications. This has made it difficult to determine whether observed structural changes in the brain are due to the illness itself or the effects of treatment. For example, people with more severe or long-standing psychotic symptoms often receive higher doses of antipsychotics over longer periods—factors that may independently influence brain structure.

To address this issue, study author Pierluigi Selvaggi and colleagues investigated the effects of repeated exposure to antipsychotics in healthy individuals using magnetic resonance imaging (MRI). They focused on two widely used antipsychotic medications: amisulpride and aripiprazole.

Amisulpride is an atypical antipsychotic that selectively blocks dopamine D₂ and D₃ receptors, particularly in limbic regions of the brain. At low doses, it can enhance dopamine activity, potentially improving mood and alleviating negative symptoms such as social withdrawal. At higher doses, it reduces dopamine signaling and can help alleviate positive symptoms like hallucinations and delusions.

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Aripiprazole, in contrast, is a dopamine partial agonist. This means it both stimulates and blocks dopamine receptors, depending on the local dopamine environment. Its unique mechanism helps stabilize dopamine activity—reducing it where dopamine is excessive and enhancing it where dopamine is low. Aripiprazole also interacts with serotonin receptors, which contributes to its antidepressant and mood-stabilizing properties.

The study involved 48 healthy volunteers of both sexes, with an average age of 27. Twenty-one were male.

Participants were randomly divided into two equal groups. One group received amisulpride; the other received aripiprazole. Within each group, participants were further randomized to take either the active drug for one week followed by a week of placebo, or vice versa. The placebo capsules were indistinguishable from the active drug to ensure that neither participants nor researchers knew which was being administered at any given time—a design known as double-blind crossover.

The results showed that one week of amisulpride led to a statistically significant increase in the volume of the left putamen and right caudate, compared to both baseline and placebo. Aripiprazole increased the volume of the right putamen compared to placebo. These volumetric changes were not observed in other brain regions, and no cortical changes were detected.

Importantly, the changes reversed within weeks of stopping the medications, indicating that the effects were transient.

“Short-term exposure to either one of two different antipsychotics results in a transient increase in striatal volume measured with T1-weighted MRI [a type of magnetic resonance imaging sequence that produces high-resolution anatomical images in which fat appears bright and fluid appears dark] that normalizes rapidly on stopping treatment without cortical changes. Our findings suggest that striatal volumetric MRI [magnetic resonance imaging] differences detected in people with schizophrenia taking antipsychotics are, at least in part, attributable to pharmacological effects,” the study authors concluded.

The study sheds light on the effects of the two studied antipsychotics on brain structure. However, it should be noted that the study was conducted on very small groups of participants meaning that only changes that were quite substantial were statistically detectable. Additionally, study participants were all healthy. Results on individuals suffering from psychotic disorders may not be identical.

The paper, “Antipsychotics cause reversible structural brain changes within one week,” was authored by Pierluigi Selvaggi, Martin Osugo, Uzma Zahid, Ottavia Dipasquale, Thomas Whitehurst, Ellis Onwordi, George Chapman, Valeria Finelli, Ben Statton, Tobias C. Wood, Matthew B. Wall, Robin Murray, Mitul A. Mehta, Tiago Reis Marques, and Oliver D. Howes.