Pharmacogenomics of drugs used to treat brain disorders

ABSTRACT

Introduction

Neuropsychiatric disorders (NPDs) (neurodevelopmental, mental, neurodegenerative, neurotoxic, complex disorders) are the third major problem of health in developed countries. About 10-20% of direct costs are attributed to pharmacological treatment; however, drug effectiveness is lower than 30% in most NPDs. Pharmacogenomics accounts for 60-90% variability in pharmacokinetics and pharmacodynamics.

Areas covered

Main areas covered include (i) organization of the pharmacogenetic machinery (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes); (ii) pharmacogenomics of antidepressants, antipsychotics, anxiolytics, antiepileptics, anti-Alzheimer, anti-Parkinson, and anti-stroke drugs; and (iii) adverse drug reactions and pharmaco-resistance.

Expert commentary

The pharmacogenomics of NPDs is still primitive, but sufficient to help physicians to optimize pharmacological treatment by reducing ADRs (extrapyramidal symptoms, tardive dyskinesia, neurotoxicity, cerebrovascular damage) and unnecessary costs. Over 50% of psychotropic drugs are incorrectly prescribed. CYP enzymes participate in the metabolism of over 90% of drugs for the treatment of NPDs. Only 20% of the population is potentially extensive metabolizer for 80% of current psychotropic agents. Consequently, the introduction of pharmacogenomic procedures in the clinical setting is an urgent need for improving drug efficacy and safety.

KEYWORDS:

• Brain disorders
• psychotropic drugs
• pharmacogenomics
• transporter genes

Article Highlights

• Central nervous system (CNS) disorders are the third major problem of health in developed countries.

• Neuropsychiatric disorders (NPDs)(mental, neurological, substance use disorders) contribute approximately 10% of the global burden of disease.

• CNS disorders can be classified into 6 major categories: (i) neurodevelopmental disorders, (ii) mental disorders, (iii) age-related neurodegenerative disorders, (iv) cerebrovascular disorders, (v) neurotoxic disorders, and (vi) other complex disorders.

• At least 13 pharmacological categories of CNS drugs can be differentiated, with over 400 drugs currently used for the treatment of brain disorders.

• The pharmacogenomic machinery is integrated by pathogenic, mechanistic, metabolic, transporter and pleiotropic genes under the regulatory control of epigenetic mechanisms (DNA methylation, histone changes/chromatin remodeling, miRNA regulation).

• Globally, 74% pathogenic, 97% mechanistic, 94% metabolic, 68% transporter and 40% pleiotropic genes have been so far associated with the efficacy and safety of antiepileptic, antidepressant, anxiolytic, hypnotic, sedative, antiparkinsonian and antipsychotic drugs.

• About 90% of CNS drugs use CYP enzymes as major metabolic pathways.

• CNS drugs are substrates, inhibitors or inducers of 58, 37 and 42 enzyme/protein gene products, and are transported by 40 different protein transporters.

• Antidepressants are substrates, inhibitors or inducers of 40, 22, and 9 enzyme/protein gene products, respectively, and are transported by 13 different protein transporters. CYP enzymes are involved in 100% of drugs approved for the treatment of depression.

• Antipsychotics are substrates, inhibitors or inducers of 32, 16 and 3 enzyme/protein gene products, respectively, and are transported by at least 14 different protein transporters. CYP enzymes participate in the metabolism of 90% of antipsychotics.

• Anxiolytics, hypnotics and sedatives are substrates, inhibitors or inducers of 47, 18 and 30 enzyme/protein gene products, and are transported by at least 30 protein transporters. CYP enzymes participate in the metabolism of over 92% of these drugs.

• Anti-PD drugs are substrates and/or inhibitors of 33 and 18 enzyme/protein gene products, respectively, and are transported by 3 transporters. CYP enzymes participate in the metabolism of 87% of anti-PD drugs.

• Antiepileptics are substrates, inhibitors or inducers of 40, 15 and 24 enzyme/protein gene products, respectively, and are transported by at least 16 protein transporters. CYP enzymes participate in the metabolism of over 69% of anticonvulsants.

• Over 80% of individuals are deficient for the biotransformation of current drugs which are metabolized via CYP2D6-2C9-2C19-3A4 enzymes.

• PGx accounts for 50-90% of variability in drug pharmacogenetics and pharmacodynamics.

• The optimization of therapeutics in CNS disorders would be enhanced with the incorporation of PGx procedures into current medical practice.

Acknowledgments

I would like to thank my collaborators at the International Center of Neuroscience and Genomic Medicine EuroEspes, Juan C. Carril, Iván Carrera, Olaia Martínez, Vinogran Naidoo, Margarita Alcaraz, Laura Nebril, Lola Corzo, Susana Rodríguez, Ramón Alejo, Lucía Fernández-Novoa, Iván Tellado, Pablo Cacabelos, Natalia Cacabelos and Adam McKay for technical assistance.

Declaration of interest

RC is President and stockholder of EuroEspes (Biomedical Research Center), EuroEspes Biotechnology, IABRA, and EuroEspes Publishing Co. RC is the inventor of Atremorine. The author has no other relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed, apart from those disclosed.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This article was funded by EuroEspes Biomedical Research Center and IABRA (International Agency for Brain Research and Aging), Corunna, Spain.