Pharmacogenetics of neurological and psychiatric diseases at older age: has the time come?

ABSTRACT

Introduction: In recent years, a number of pharmacological approaches for treating neuropsychiatric conditions at older age have proven to be inadequate. The resulting increased prevalence of therapeutic failures (TF) and a worsening of clinical symptoms often linked to adverse reactions (ADRs), are perhaps among the major causes of the increasing rate of hospitalizations and institutionalizations observed in these patients.

Areas covered: This review underlines the importance of pharmacogenetic data to fingerprint the pharmacological treatment of neuropsychiatric late-life conditions throughout the analysis of metabolizing enzymes and transporters of psychotropic drugs, mainly those of the cytochrome P450 (CYP) family. Pharmacodynamic response measures as treatment effects mediated through targets (i.e., receptors in the brain) may also contribute to this image.

Expert opinion: CYP genetics is the basis of a continuum on which environmental and physiological factors act, modeling the phenotype observed in clinical practice with advancing age. Furthermore, other specific polymorphic genes influence drug response through differential effects of their functional genetic variants. The known genotypes associated with an altered metabolizer status and drug transporters may help clinical decision-making to avoid concomitant treatments, reduce therapeutic attempts and increase drug safety in neuropsychiatric conditions in older age, after controlling for other clinical variables.

KEYWORDS:

• Therapeutic failure
• adverse drug reaction
• psychiatric disorders
• pharmacogenetics
• cytochrome P450
• CYP2D6
• 5-hydroxytriptamine transporter
• 5-HTT
• dopamine transporter
• DAT

Article highlights

• Neuropsychiatric syndromes at older age are characterized by severe disturbances in mood and behavior and abnormal thinking, leading to significant mental and social impairments with an increased risk of hospitalization and disability worldwide

• The tendency of older people to develop adverse drug reactions (ADRs) to psychoactive medications is often due to physiological pharmacokinetics and pharmacodynamics changes associated with aging and comorbidity

• Although pharmacological evidenced-based treatment guidelines include a wide range of medications, such as first and second-generation antipsychotics, mood stabilizer and antidepressants also in multi-drug combinations, treatment response is often inadequate, and the rate of remission is poor

• The genetics of drug metabolizing enzymes and drug transporters is a very active area of pharmacogenetic research, because these proteins are virtually responsible for drug metabolism and target site of action, and thus contribute to the efficacy of a number of drugs currently used in clinical practice

• The drug selection decision process thus might embody a higher degree of sophistication based on increased technologic advancements and discoveries, e.g., cytochrome P450 (CYP)P2D6 isoenzymes and 5-HT transporter polymorphisms

• Although the controversial cost-effectiveness of genotyping, tests for structural variants in the genes for CYP isoenzymes and for polymorphisms of neurotransmitter transporters and receptors may identify individuals with a greater or lesser likelihood of responding to and tolerating psychotropic medications.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This study was completely supported by ‘ Ministero della Salute’, I.R.C.C.S. Research Program, Ricerca Corrente 2015-2017, Linea n. 2 ‘Malattie complesse e terapie innovative’ and by the ‘5 × 1000’ voluntary contribution.