Porcelli, S., Drago, A., Fabbri, C., Gibiino, S., & Calati, R., Serretti, A. (2011). Pharmacogenetics of antidepressant response. Journal of Psychiatry & Neuroscience, 36(2), 87–113. https://doi.org/10.1503/jpn.100059

References for SSRIs and Low Threshold Responders

The SLC6A4 gene encodes the serotonin transporter (5-HTT), which is responsible for reuptake of serotonin from the synaptic cleft back into presynaptic neurons. This transporter is the primary target of SSRIs. The 5-HTTLPR polymorphism in the gene promoter has two main alleles:

Short (S) allele: Associated with reduced transcriptional efficiency: fewer serotonin transporters expressed.

Long (L) allele: Higher expression of transporters.

Individuals with the S/S genotype have significantly reduced transporter expression compared to L/L or L/S genotypes.

This can cause:

Reduced SSRI efficacy

Increased risk of side effects (such as mood instability, agitation, anxiety, insomnia, and emotional distress or blunting) and can also be linked to bipolar symptoms with rapid mood cycling

SLC6A4 Gene

The HTR2A gene encodes the 5-HT2A receptor which is a key serotonin receptor. It plays a role in mood regulation, sleep, anxiety, and emotional processing. SSRIs indirectly affect this receptor by increasing extracellular serotonin.

Two commonly studied HTR2A polymorphisms that affect SSRI response and sensitivity are rs6311 (−1438G/A) and rs6313 (102T/C).

The G/G genotype of rs6311 is associated with lower 5-HT2A receptor density, meaning that there are fewer serotonin 2A receptors in a specific region of the brain. This may cause blunted emotional response/apathy and lower SSRI efficiency, which can lead the individual to be labeled as treatment resistant due to their lack of emotional responsiveness. 

The rs6313 (102T/C) mutation is highly similar to the rs6311 allele where (C/C) may lead to jitteriness or impulsivity.

Overall, low threshold responders with these polymorphisms may show hypersensitivity to serotonergic modulation and experience opposite reactions (worsening of anxiety or insomnia instead of helping it), which can lead to the patient discontinuing treatment.

HTR2A Gene

The CYP2C19 gene provides instructions for producing an enzyme that is primarily involved in the metabolism of several medications, including certain SSRIs.

Poor Metabolizers (2/2 or 3/3 genotypes):
These individuals have two nonfunctional alleles, resulting in very little or no CYP2C19 enzyme activity. This leads to slower drug metabolism, higher plasma concentrations, and greater risk of side effects, such as sedation, nausea, or emotional blunting. Poor metabolizers may experience exaggerated side effects or toxicity at standard doses due to an impairment in drug clearance.

Intermediate Metabolizers (1/2): Reduced enzyme function. Individuals may still metabolize drugs but at a slower rate than normal.

Ultrarapid Metabolizers (17/17): Increased enzyme activity leads to faster clearance of SSRIs which can reduce effectiveness. Ultrarapid metabolizers may receive less of a therapeutic benefit unless the dose is increased.

CYP2C19 Gene

The CYP2D6 gene encodes a liver enzyme that plays a role in metabolizing multiple SSRIs. There are many different genetic variants that affect enzyme activity and drug metabolism.

Poor Metabolizers (4/5 genotypes):
These individuals lack functional CYP2D6 activity which results in slower metabolism of SSRIs like paroxetine and fluoxetine. This also leads to elevated drug levels, which can cause side effects such as sedation, agitation, nausea, or emotional blunting. Poor metabolizers are more prone to intolerance or toxicity at standard doses.

Ultrarapid Metabolizers (multiple copies of 1 or 2 alleles):
These individuals have increased CYP2D6 activity, metabolizing SSRIs too quickly. This leads to low plasma concentrations and reduced therapeutic effect. Individuals with this genotype may be mistaken as treatment resistant due to poor response at normal doses.

CYP2D6 Gene

The COMT gene encodes an enzyme that breaks down dopamine in the prefrontal cortex. A common polymorphism in this gene is Val158Met (rs4680), which alters the activity of the COMT enzyme and influences dopamine levels in the brain.

Met/Met genotype: This genotype leads to low COMT enzyme activity, resulting in higher levels of dopamine in the prefrontal cortex. Individuals  with this genotype may be more sensitive to serotonin and dopamine interactions, and are at increased risk of agitation, overstimulation, or emotional reactivity when treated with SSRIs.

Val/Val genotype: This genotype produces a high-activity form of the COMT enzyme, leading to lower dopamine levels in the prefrontal cortex. Individuals with this genotype experience a blunted antidepressant response, slower symptom improvement, and may be perceived as treatment resistant due to reduced emotional responsiveness during SSRI treatment.

COMT Gene

Selective Serotonin Reuptake Inhibitors, also known as SSRIs, is one of the most commonly prescribed antidepressant. However, unlike regular individuals, low threshold responders often experience amplified side effects or poor efficacy even at low doses which may cause it to be more harmful than helpful. These hypersensitive reactions are frequently rooted in genetic polymorphisms affecting serotonin transport, metabolism, and brain sensitivity to serotonergic stimulation.

Ohio State University, Columbus

Low threshold responders are individuals who experience a type of drug hypersensitivity that causes amplified or abnormal effects from medications and psychoactive substances which are caused by biological and genetic sensitivities. These individuals have abnormal responses to antidepressants, antipsychotics, stimulants, sedatives, and recreational substances like caffeine, alcohol, cannabis, and psychedelics. Unlike general adverse drug reactions which can be sudden and unexpected, low threshold responders have a predictable pattern of intolerance to multiple substances due to neurotransmitter imbalances, slowed metabolism, or receptor sensitivity. 

The biggest cause of this is due to mutations in specific genes that regulate dopamine, serotonin, or other neurotransmitter responses, especially when given anything that changes the levels of neurotransmitters in the brain. These individuals are often mislabeled as treatment resistant as they may develop an intolerance to substances that impact neurotransmission or may have a heightened response to these substances.

Low Threshold Responders: Drug Hypersensitivity

Malhotra, A. K., Murphy, G. M., & Kennedy, J. L. (2004). Pharmacogenetics of psychotropic drug response. American Journal of Psychiatry, 161(5), 780–796. https://doi.org/10.1176/appi.ajp.161.5.780

GeneSight® Psychotropic Report White Paper. (n.d.). Interpreting the GeneSight Psychotropic Combinatorial Pharmacogenomic Test Report.
https://genesight.com/white-papers/interpreting-the-genesight-psychotropic-report

 References for Low Threshold Responders: Drug Hypersensitivity

SSRIs and Low Threshold Responders

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.

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