The Complex Picture of Brain Volume Changes
For decades, scientists have grappled with a complex question: how does antipsychotic medication affect the brain's physical structure? Early findings of smaller brain volumes in patients with schizophrenia were initially attributed to the illness itself, but later research revealed that medication also plays a role. Compounding the issue is that both the illness and the treatment are intertwined. Active psychosis, untreated illness duration, and factors like substance use can also contribute to changes in brain volume. This makes it notoriously difficult for researchers to disentangle what specific changes are caused by medication versus the underlying condition or other lifestyle factors. Observational studies, while informative, are prone to biases, whereas controlled trials have their own limitations, including ethical considerations for untreated control groups. The result is a nuanced picture where antipsychotics appear to cause specific structural changes, which may or may not be clinically adverse, and sometimes even coincide with improved function.
Subcortical Volume Changes (Basal Ganglia)
Some of the most consistent findings regarding antipsychotic-induced brain changes involve the basal ganglia, a subcortical region of the brain involved in motor control, emotion, and reward. Studies have repeatedly observed an increase in the volume of the basal ganglia—specifically the striatum (caudate and putamen) and pallidum—in patients on antipsychotics. This effect appears to be dose-dependent and linked to the drugs' primary mechanism of blocking dopamine D2 receptors.
A recent placebo-controlled study in healthy volunteers found that just one week of treatment with certain antipsychotics led to a reversible increase in striatal volume. This suggests the effects can be rapid and temporary, and may be part of the drug's therapeutic action rather than a sign of irreversible damage. The pallidal volume increase has also been associated with greater symptom reduction in some first-episode psychosis patients, suggesting a link between this change and clinical benefit.
Cortical and White Matter Variations
The picture is more contentious when it comes to the cortex, the brain's outer layer responsible for higher-level functions. Numerous longitudinal studies have reported an association between higher cumulative antipsychotic exposure and a decrease in cortical grey matter volume over time, particularly in frontal and parietal regions. However, this is heavily debated, as cortical thinning is also seen in patients with schizophrenia who have experienced untreated psychosis or relapse, complicating the attribution.
Findings on white matter, which facilitates communication between brain regions, are also inconsistent. Some studies link higher antipsychotic doses to white matter volume reductions, while others suggest lower doses might lead to modest increases. One study even found that a long-acting injectable (LAI) formulation of an antipsychotic was associated with stable or increased white matter volume compared to oral medication.
The Role of Neuroplasticity
The observed structural changes are not necessarily a sign of brain damage or cell death. Many researchers propose they are a manifestation of neuroplasticity, the brain's ability to reorganize itself. Antipsychotics can influence synaptic connections, cellular processes, and gene expression, which could contribute to the observed volumetric shifts. Some studies have even reported cognitive improvements in patients despite observing volumetric changes, highlighting that size is not the sole determinant of function. The changes may reflect an adaptive or compensatory response to the drug's action, rather than a harmful effect.
Comparative Effects of Antipsychotic Generations
While studies have not consistently shown that second-generation antipsychotics are universally superior in terms of brain effects, there are distinctions in their impact on structure.
| Feature | First-Generation (Typical) Antipsychotics | Second-Generation (Atypical) Antipsychotics |
|---|---|---|
| Primary Mechanism | Strong D2 receptor antagonism in the striatum | Broader receptor profiles, lower D2 affinity |
| Striatal Volume | Stronger association with increases in caudate and putamen | Milder or potentially no increase in striatal volume in some studies |
| Cortical Volume | Some studies link to more prominent cortical grey matter loss | Conflicting results; some studies suggest less loss or even protective effects |
| Extrapyramidal Side Effects | Higher risk of movement disorders like tardive dyskinesia | Lower risk, though still a possibility with long-term use |
Weighing the Risks and Benefits
It is crucial to recognize that the evidence linking antipsychotic treatment to structural brain changes is complex and sometimes contradictory. What remains unequivocally clear from clinical trials is that antipsychotic medication is highly effective at managing psychosis and preventing relapse, which in itself has neurotoxic effects. Given that untreated psychosis and relapse are associated with negative brain changes and poor outcomes, the widely accepted practice is to use the lowest effective dose to minimize side effects while maximizing therapeutic benefits. This evidence supports a careful, individualized approach to treatment, rather than general recommendations against medication.
Conclusion
The question of whether antipsychotics change brain structure has evolved from a simple yes/no inquiry into a more nuanced understanding of neuroplasticity, illness effects, and pharmacological mechanisms. Antipsychotics do cause measurable structural changes, including increases in subcortical volumes and potential decreases in cortical volumes, but the clinical significance of these alterations is still under debate. Some effects appear to be transient and possibly part of the therapeutic process, while other long-term changes are difficult to disentangle from the effects of the underlying illness and other confounding factors. Ultimately, for patients dealing with psychosis, the benefits of effective treatment and relapse prevention generally outweigh the potential risks associated with medication-related structural changes. Continued research is vital to further illuminate these complex interactions and guide personalized treatment approaches.
For additional context on the neurobiological underpinnings of this debate, a review article can be found here.
