The usual drugs used to treat mental disorders are often ineffective. Consideration of genetic variants and pharmacogenetic biomarkers enables personalized drug therapy that works better and avoids adverse drug reactions, especially for antidepressants and antipsychotics.
Mental health is of crucial importance for personal well-being, interpersonal relationships and social participation. Mental illness affects physical health, causes pain and disability and, in extreme cases, can lead to suicide. In connection with mental illness, suicide is one of the most common causes of death in the western world.
In the United States, neuropsychiatric disorders are responsible for 19% of all years of life lost due to illness and premature mortality. Among the most important mental illnesses are schizophrenia and depression, which together affect more than 300 million people worldwide.
The drugs commonly used to treat psychiatric disorders often have adverse effects. Large randomized clinical trials (RCTs) have shown that only a limited number of people with psychiatric disorders benefit from treatment with antidepressants. In particular, patients with major depressive disorder, which affects 163 million people worldwide, the response rate to psychotropic drugs is only 42-53%. There is therefore a great need to improve both the response rate and the effect of currently available medication.
What does the efficacy of psychotropic drugs depend on and what can pharmacogenetics contribute?
The reaction of patients to psychotropic drugs varies considerably. This is due to genetic, environmental, pathophysiological and nutritional factors. Of these, interactions between drugs and differences in genetic constitution are particularly relevant. Certain genetic variants influence the effect of drugs and serve as pharmacogenetic biomarkers. If the specific genetic profile of a patient is known, the medication can be individually adapted and trial-and-error situations avoided. This improves efficacy and avoids adverse drug reactions.
How does genetics influence the efficacy of antidepressants?
The antidepressants of the classes SSRI (serotonin reuptake inhibitors; e.g., sertraline, paroxetine) and TCA (tricyclic antidepressants; e.g., amitriptyline) are metabolized by the enzymes CYP2D6 and/or CYP2C19. Decreased enzyme activity may result in delayed degradation of the drug, which in turn may result in increased concentration at a standard recommended dose and the occurrence of adverse drug reactions. Increased enzyme activity, on the other hand, may result in insufficient drug levels at a standard dosage due to more rapid degradation of the drug, and drug effects may not occur.
How do genetics influence the efficacy of antipsychotics?
Like antidepressants, antipsychotics (e.g., aripiprazole, brexpiprazole, haloperidol, or risperidone) are also influenced in their effect by genetic variants in the CYP2D6 gene and the resulting deviating enzyme activation.
[3] Brown, L. C. et al. (2022). Pharmacogenomic Testing and Depressive Symptom Remission: A Systematic Review and Meta-Analysis of Prospective, Controlled Clinical Trials. Clinical Pharmacology & Therapeutics. https://doi.org/10.1002/cpt.2748
