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

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

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.

SSRIs and Low Threshold Responders

 References for Low Threshold Responders: Drug Hypersensitivity

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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