Güzey, C., Scordo, M. G., Spina, E., Landsem, V. M., & Spigset, O. (2007). Antipsychotic-induced extrapyramidal symptoms in patients with schizophrenia: Associations with dopamine and serotonin receptor and transporter polymorphisms. European Journal of Clinical Pharmacology, 63(3), 233–241. https://doi.org/10.1007/s00228-006-0234-8

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Wikipedia contributors. (2024, July 10). Antipsychotic. Wikipedia. https://en.wikipedia.org/wiki/Antipsychotic

Ohio State University, Columbus

Antipsychotics are a class of psychiatric medications that are used to manage symptoms of psychosis such as hallucinations, delusions, and disorganized thinking, and are commonly prescribed for conditions such as schizophrenia and bipolar disorder. They usually work by antagonizing D2 dopamine receptors. However, low threshold responders often experience amplified side effects or poor tolerability even at standard or reduced doses, which may make treatment more harmful than helpful. These reactions are usually caused by genetic polymorphisms affecting dopamine and serotonin receptor function or drug-metabolizing enzymes.

Antipsychotics and Low Threshold Responders

The DRD2 gene encodes the dopamine D2 receptor which is the main target for many antipsychotic medications.

A1 Allele Carriers (A1/A1 variant): Individuals with the A1 allele have reduced D2 receptor density in brain regions such as the striatum, which can lead to heightened sensitivity to the antagonistic effects caused by Antipsychotics on the D2 receptor. As a result, these individuals are more likely to experience extrapyramidal symptoms (EPS) such as tremors, rigidity, and akathisia, even at low doses. Overall, those who carry the A1 allele of the DRD2 gene may require dose adjustments or other therapies to avoid these side effects as EPS such as TD which can be permanent.

DRD2 Gene

The DAT1 gene (also called SLC6A3) encodes the dopamine transporter (DAT) which is a protein responsible for reuptake of dopamine from the synaptic cleft into presynaptic neurons. A variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region (3′ UTR) of DAT1 has been studied for its role in dopamine regulation, psychiatric disorders, and response to psychotropic medications.

9R/9R Genotype (Homozygous 9R): This genotype is associated with lower DAT expression compared to 10R. This leads to higher synaptic dopamine availability. It is linked to traits such as impulsivity, novelty-seeking, and sometimes greater sensitivity to stimulant medications and may increase vulnerability to substance use disorders.
Could cause heightened sensitivity to dopamine-blocking antipsychotics. Individuals may experience extrapyramidal symptoms (EPS), akathisia, agitation, or sedation even at low doses.

10R/10R Genotype (Homozygous 10R): This genotype is associated with higher DAT expression. It results in increased dopamine reuptake and reduced extracellular dopamine levels. Some studies suggest associations with attention-deficit/hyperactivity disorder (ADHD) and altered reward sensitivity. Individuals with this mutation may show different response patterns to stimulant and antipsychotic treatment.
Individuals with this genotype may show reduced sensitivity to antipsychotics, potentially requiring higher doses to achieve therapeutic effects. Could experience blunted emotional response or appear treatment resistant.

DAT1 (SLC6A3) VNTR Gene

The COMT gene encodes catechol-O-methyltransferase which is an enzyme that plays a part in dopamine degradation in the prefrontal cortex, where dopamine transporters are scarce. The Val158Met (rs4680) polymorphism can alter COMT activity, which influences dopamine availability and antipsychotic response.

Met/Met (A/A at rs4680, low-activity COMT): Linked with higher prefrontal dopamine due to reduced enzyme activity. Met/Met individuals may have elevated dopamine tone that can enhance cognitive function but may reduce the tolerability to dopaminergic agents like antipsychotics. Additionally,  some studies show that Met allele carriers have significantly improved antipsychotic responses.

Val/Val (G/G at rs4680, high-activity COMT): This genotype is associated with lower dopamine levels due to higher enzyme activity. Val/Val individuals often show better cognitive improvement with dopaminergic agents but may have less benefit from antipsychotics targeting the dopamine system. Some research (Huang et al., 2016) shows reduced treatment efficacy for Val/Val carriers when compared to Met/Met, especially with atypical antipsychotics.

Val/Met (A/G heterozygotes): Shows intermediate COMT activity and dopamine levels: clinically non-actionable, individuals have typical medication tolerability.

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