How do antipsychotics change the brain? A Look at Structure, Function, and Long-Term Effects

October 7, 2025 •

4 min read

In the United States, approximately 1.6% of adults use antipsychotic medications, which are essential for treating conditions like schizophrenia and bipolar disorder [1.8.1, 1.8.2]. Understanding how do antipsychotics change the brain is crucial for weighing their therapeutic benefits against potential long-term effects on neural structure and function.

Quick Summary

Antipsychotic medications primarily work by modulating dopamine and serotonin pathways to manage psychosis. These drugs can induce both beneficial and adverse changes in brain structure and function, including alterations in gray matter volume and neuroplasticity.

Key Points

Dopamine Blockade: Antipsychotics primarily work by blocking dopamine D2 receptors in the brain to reduce psychotic symptoms [1.5.3].
Structural Changes: Long-term use, especially at high doses, is associated with reductions in gray and white matter volume [1.2.1, 1.2.2].
Generational Differences: Second-generation antipsychotics (SGAs) also target serotonin receptors, offering a broader efficacy and different side-effect profile than first-generation (FGAs) drugs [1.3.2, 1.4.6].
Neuroplasticity: SGAs may have neuroprotective or neurogenic (promoting new cell growth) effects, while some FGAs have been linked to neurotoxicity [1.9.1, 1.9.3].
Tardive Dyskinesia Risk: Chronic dopamine receptor blockade can lead to receptor hypersensitivity, causing the involuntary movement disorder tardive dyskinesia [1.7.2].
Benefit vs. Risk: The brain changes are complex, and treatment involves balancing the medication's therapeutic necessity against potential adverse effects like volume loss and movement disorders [1.6.2].
Basal Ganglia Impact: Brain regions rich in D2 receptors, like the striatum, are particularly affected, with some studies showing volume increases that may relate to both therapeutic and side effects [1.6.4, 1.9.2].

The Core Mechanism: Targeting Brain Neurotransmitters

Antipsychotic medications exert their primary influence by interacting with the brain's neurotransmitter systems, especially dopamine and serotonin [1.3.1, 1.3.2]. Psychotic symptoms are often linked to a hyper-responsive dopamine system [1.3.6]. Antipsychotics work to correct this imbalance.

Dopamine D2 Receptor Blockade

The hallmark of most antipsychotics is the blockade of dopamine D2 receptors [1.5.3].

First-Generation Antipsychotics (FGAs): Also known as 'typical' antipsychotics, these drugs are potent dopamine D2 receptor antagonists [1.3.1]. By blocking a significant percentage of these receptors (ideally 65-80%), they reduce the flow of dopamine messages in the brain's mesolimbic pathway, which helps alleviate 'positive' symptoms like hallucinations and delusions [1.3.1, 1.3.3]. However, this blockade is not selective and also affects dopamine pathways controlling movement, leading to extrapyramidal side effects (EPS) [1.5.1].
Second-Generation Antipsychotics (SGAs): Termed 'atypical' antipsychotics, these newer drugs also block D2 receptors but often with a lower affinity or for a shorter duration [1.3.1, 1.5.4]. Crucially, they also act on other receptors, most notably serotonin 5-HT2A receptors [1.3.2, 1.4.4]. This dual action is thought to contribute to their effectiveness against 'negative' symptoms (like emotional withdrawal) and a lower risk of certain motor side effects compared to FGAs [1.4.6].

Structural Brain Changes: A Complex Picture

Long-term antipsychotic treatment is associated with measurable changes in brain structure, though it's a complex area of study that must also account for the effects of the underlying illness itself [1.2.1, 1.2.2].

Gray and White Matter Volume

Multiple longitudinal studies have investigated the relationship between antipsychotic use and brain volume. A large-scale study found that a greater intensity of antipsychotic treatment was associated with smaller gray matter volumes over time [1.2.1, 1.2.2]. Progressive decreases in white matter volume were also more evident in patients receiving higher doses of antipsychotics [1.2.1].

Some research suggests these changes might be dose-related. One study noted that patients on low-dose antipsychotics tended to show modest increases in white matter volume over time, compared to volume loss in those on higher doses [1.2.3]. The specific class of drug may also play a role. For instance, higher doses of typical antipsychotics have been linked to smaller frontal gray matter volumes, while some atypical antipsychotics are associated with changes in other areas [1.2.1]. It remains a critical area of research to disentangle the effects of the medication from the progression of the illness, as untreated psychosis is also linked to brain volume loss [1.6.2].

Basal Ganglia Alterations

Certain brain regions, like the basal ganglia (which includes the striatum), are particularly affected due to their high density of D2 receptors [1.9.2]. Some studies have reported an increase in the size of the striatum in individuals taking certain antipsychotics [1.6.4]. These changes may be linked to both the therapeutic effects of the drugs and their potential to cause motor side effects [1.6.5].

Functional and Neuroplastic Adaptations

Beyond large-scale structural changes, antipsychotics also influence the brain's functional connectivity and capacity for neuroplasticity—the ability to reorganize itself.

Neuroplasticity and Neurogenesis: The brain's ability to form new connections and even new neurons (neurogenesis) is a key area of research. Atypical antipsychotics (SGAs) have shown a more consistent profile of enhancing neurogenesis in animal studies compared to typical antipsychotics (FGAs) [1.9.1]. For example, SGAs like olanzapine and risperidone have been found to stimulate the proliferation of new cells in brain regions like the hippocampus and prefrontal cortex [1.9.3, 1.9.5]. In contrast, some studies suggest typical antipsychotics like haloperidol can be neurotoxic at high doses and may reduce levels of Brain-Derived Neurotrophic Factor (BDNF), a key protein for neuron survival and growth [1.9.1, 1.9.3].
Functional Connectivity: Antipsychotics can normalize or alter patterns of brain activity [1.2.5]. For instance, they can impact the Default Mode Network (DMN), a network of brain regions active during rest, which is often disrupted in schizophrenia [1.2.6]. By modulating these networks, antipsychotics may help improve symptoms.

Comparison of Antipsychotic Generations


Feature	First-Generation (Typical) Antipsychotics	Second-Generation (Atypical) Antipsychotics
Primary Mechanism	Potent Dopamine D2 receptor blockade [1.3.1, 1.4.4].	Dopamine D2 and Serotonin 5-HT2A receptor blockade [1.3.2, 1.4.4].
Symptom Efficacy	Primarily effective for positive symptoms (hallucinations, delusions) [1.3.1].	Effective for both positive and negative symptoms (apathy, social withdrawal) [1.4.6].
Motor Side Effects	Higher risk of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) [1.4.6, 1.5.1].	Lower risk of EPS and TD, but risk is still present [1.3.1, 1.4.2].
Metabolic Side Effects	Lower risk of significant weight gain and metabolic syndrome [1.4.2].	Higher risk of weight gain, diabetes, and other metabolic issues [1.4.2].
Brain Volume Effects	Associated with gray matter reduction; may be more pronounced than with some SGAs [1.2.1, 1.9.3].	Effects are variable; some studies suggest they are less associated with gray matter loss than FGAs [1.9.3].

The Risk of Tardive Dyskinesia (TD)

One of the most significant long-term risks of antipsychotic treatment is tardive dyskinesia, a movement disorder characterized by involuntary, repetitive body movements [1.7.5]. The prevailing hypothesis is that chronic D2 receptor blockade leads to an upregulation and hypersensitivity of these receptors in the nigrostriatal pathway of the brain [1.7.2]. When dopamine is present, this supersensitive system overreacts, resulting in the characteristic hyperkinetic movements [1.7.2]. Other proposed mechanisms include oxidative stress and neurotoxicity from increased dopamine turnover [1.7.3, 1.7.4]. The risk is generally higher with first-generation antipsychotics due to their potent and sustained D2 blockade [1.7.3].

Conclusion

Antipsychotics fundamentally change the brain by modulating key neurotransmitter systems, which can lead to significant therapeutic benefits for individuals with psychotic disorders. These changes extend from the molecular level of receptor binding to large-scale shifts in brain volume and functional connectivity. While newer atypical antipsychotics offer a broader range of action and a potentially better side-effect profile regarding motor symptoms, they are associated with metabolic risks. The long-term use of any antipsychotic requires a careful and continuous evaluation of its benefits versus the risks, including structural brain changes and the potential for movement disorders like tardive dyskinesia. The goal is always to use the lowest effective dose for the necessary duration to manage symptoms while minimizing adverse effects [1.2.3, 1.6.2].

For further reading, consider this authoritative resource from the National Institutes of Health: Long-term Antipsychotic Treatment and Brain Volumes [1.2.1]

Frequently Asked Questions

Some studies indicate that long-term, high-dose antipsychotic use is associated with a reduction in gray matter volume [1.2.1, 1.2.2]. However, it is a complex issue, as the underlying mental illness itself can also contribute to brain volume changes. The goal is to use the lowest effective dose to minimize this risk [1.6.2].

Typical (first-generation) antipsychotics mainly block dopamine D2 receptors [1.3.1]. Atypical (second-generation) antipsychotics block both dopamine D2 and serotonin 5-HT2A receptors, which often results in a lower risk of motor side effects and better efficacy for negative symptoms [1.3.2, 1.4.6].

Some brain changes induced by antipsychotics may be reversible. For example, animal studies have shown that striatal volume increases can reverse after discontinuing the medication [1.9.5]. However, other changes, such as those related to tardive dyskinesia, are often permanent [1.7.1].

Tardive dyskinesia (TD) is a medication-induced movement disorder featuring involuntary, repetitive movements [1.7.5]. It's believed to be caused by long-term blockade of dopamine D2 receptors, which leads to them becoming overly sensitive to dopamine [1.7.2].

Yes, antipsychotics can alter brain connectivity. They have been shown to impact networks like the Default Mode Network (DMN), which is often disrupted in schizophrenia. By modulating these networks, they can help alleviate symptoms [1.2.5, 1.2.6].

Second-generation antipsychotics (SGAs) generally have a lower risk of causing severe motor side effects like tardive dyskinesia [1.4.2]. Some research also suggests they may be less associated with gray matter loss and may even have neuroprotective properties compared to first-generation drugs [1.9.3]. However, SGAs carry a higher risk of metabolic side effects [1.4.2].

The initial chemical effects, like receptor blockade, happen very quickly. However, the therapeutic actions and more significant structural and neuroplastic changes, such as the development of depolarization block or changes in synapse density, often occur over several days to weeks of consistent treatment [1.3.6, 1.9.2].