Psychotropic drugs and CYP2D6 in late-life psychiatric and neurological disorders. What do we know?

ABSTRACT

Introduction: Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the ‘engine room’ of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations.

Areas covered: The genetics of CYP and how it may be used for the management of the outcomes of the most frequent drugs (antidepressants, antipsychotics, anticholinesterase inhibitors, and anxiolytics) used in LLPND.

Expert opinion: Tailored CYP-based pharmacological treatments of LLPND will reduce TFs and ADRs, improving patient’s life, reducing number and dosage of administered drugs, and the number and duration of hospital readmissions, saving costs for clinical management of LLPND. Pharmacokinetic interactions are less predictable than pharmacodynamic ones and several requests are made to regulatory organisms for the pharmacological management of frail older patients affected by LLPND.

KEYWORDS:

• Adverse drug reaction
• cytochrome P450
• late-life neurological disorders
• late-life psychiatric disorders
• therapeutic failure

Article highlights

• Late-life psychiatric and neurological disorders (LLPND) are interesting pharmacogenetic models since did not respond sufficiently to acute treatment, showing therapeutic failures (TFs) regardless of the initial choice of medication or suffer from severe adverse drug reactions (ADRs) with worsening of clinical symptoms.

• Inappropriate medications may raise the prevalence of TFs, an important clinical condition still underestimated, and ADRs, the later also across drug-drug interactions.

• Pharmacogenetic data fingerprint the phenotypic response to drug treatments in patients with LLPND, thus began the gold standard for stratified or personalized therapeutic interventions.

• An age-related increased comorbidity, responsible for an increasing number of concomitant therapies, is a main cause of ADRs and TFs, but not sufficient to justify the increased prevalence of these severe responder phenotypes observed in geriatric practice, particularly in patients with LLNPD.

• More form of age-linked variability further than genetic ones must be considered also remaining focused on Cytochrome P450 (CYP) system.

• Significant variation in CYPs activities has been found during development, from the prenatal period up to the geriatric period

• Only 25% to 60% of drugs included in the polypharmacy administered to the elderly are successful

• Changes in the drug metabolizing activity of CYP may be the cause of unexpected and serious ADRs as well as inadequate therapeutic effects.

• We can speak of precision medicine when personalized medicine identifies a number of individuals sharing common environmental and genetic characteristics, and thus undergoing the same treatment.

• There are few prospective trial data about an individualized risk assessment including pharmacogenetic information to increase patient safety.

This box summarizes key points contained in the article

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper has not been funded.