Date of Award

2020

Document Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

James Fogleman

Second Advisor

Phil Danielson

Third Advisor

Robert Dores

Keywords

Akathisia, CYP450, Homicide, Polymorphism, Suicide, Toxicology

Abstract

From the start of the use of psychoactive prescription medications in the 1950s, physicians reported paradoxical adverse reactions, ranging from newly developing depressions to an increase in existing mood disorders, and extremely violent and bizarre acts of suicide and homicide. In this research, it is hypothesized that the pharmacological properties of the prescribed drugs or the interaction between the drugs and the enzymes that are primarily responsible for their metabolism (cytochrome P450s) could cause these reactions. Given that acts of violence could be medication-induced, the role of the rate of drug metabolism is discussed. Genetic testing of certain CYP450s could be helpful in preventing the emergence of acts of violence. Genotyping is a powerful tool in determining metabolic rates, but there are complicating issues, e.g., substrate specificity, enzyme promiscuity, unreliability of the probe used for phenotesting, phenoconversion, heterogeneity of CYP450 enzyme activity in different organs, and altered sensitivity to inhibition. The best way to estimate the possible metabolic rate is by combining genotyping, phenotyping, and therapeutic drug monitoring, in addition to carefully observing and listening to the patient.

In this dissertation, three cases studies are presented in which the combination of variant alleles and psychoactive medication may have led to extreme acts of violence. In addition, a comparative study of violent offenders versus a control group indicates four risk factors for developing an altered emotional state which can develop into acts of violence:

• More than 4 variant alleles for CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.

• Three or more prescription medications, especially when an antidepressant or other psychoactive medication is prescribed.

• An intermediate phenotype for CYP3A4.

• Fluctuating levels of psychoactive medication in the blood.

The guidelines set by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) do not apply in cases of polypharmacy or when there is more than one-drug-one gene interaction involved. An easy-to-use protocol is described that could be used in general practice by prescribing physicians to reduce the risk of dangerous side effects.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Provenance

Received from ProQuest

Rights holder

Selma Jolanda Eikelenboom-Schieveld

File size

314 p.

File format

application/pdf

Language

en

Discipline

Genetics, Pharmacology, Mental health

Available for download on Saturday, April 23, 2022

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