Readers of this website might be aware that antidepressants can cause suicide, other violent behavior and even homicide. These can be side effects or adverse drug reactions from the medication taken. Not only can antidepressants cause these side effects, but basically every psychoactive medication can put patients at risk. Few people may know that there are DNA tests that can identify individuals who might be prone to these adverse drug reactions.

To understand what kind of information such a test would provide, it might be helpful to explain the science behind these DNA tests.

In general, human cells contain 23 pairs of chromosomes. The father donates half of the chromosomes; the other half comes from the mother. Every chromosome contains many genes. A gene is the part of the DNA that codes for proteins, and proteins cause hereditary characteristics to be expressed. A gene can have two forms, called alleles. If someone inherits the same allele from the father and the mother, the person is called homozygous for that trait; if they are different, the person is heterozygous.

Medication needs to be metabolized to be expelled from the body. This is done by certain proteins called enzymes. Most medications that interact with brain chemistry are metabolized by an enzyme system called Cytochrome P450 (also known as CYP450 or P450). There are many different P450 enzymes, and they are divided into families and subfamilies. Cytochrome P450 family names are denoted by an Arabic number (e.g., CYP2), the subfamily by a Roman uppercase letter (e.g., CYP2D), and the individual enzymes by another Arabic number (e.g., CYP2D6). The alleles are indicated with an asterisk and a number, separated by a forward slash.

If someone inherited the same allele from both his father and his mother, this could be, for example, CYP2D6 *1/*1. If someone has been given two different alleles from his parents, you get two different numbers, e.g. CYP2D6 *1/*3.

While an individual normally has only two alleles for each gene, there may be many different alleles that are possible for that gene, a situation that is known as genetic polymorphism. This genetic variability in specific P450 enzymes may influence a patient’s response to prescribed drugs, including antidepressants.

If somebody has two normal alleles (known as “wild type”), such persons are generally referred to as “Extensive Metabolizers.” Not all alleles produce enzymes that are equal in their biochemical ability. Variant alleles usually encode P450 enzymes that have reduced or no activity. People possessing these alleles are called “Intermediate Metabolizers,” and, if the alleles have no, or virtually no, activity, they are designated “Poor Metabolizers.” Some variant alleles produce enzymes that metabolize at a significantly higher rate than normal, and individuals with those alleles are referred to as “Ultra-Rapid” metabolizers.

The efficacy of the Cytochrome P450 enzyme system is additionally influenced by factors such as age, sex, other diseases and extrinsic factors such as diet, smoking, substance abuse (drugs, caffeine, alcohol) and co-medications. These different reactions can result in significant drug-drug and drug-gene interactions, which can lead to unexpected side effects and/or therapeutic failure.

If a drug is not metabolized and expelled from the body, it will accumulate. This could lead to intoxication and adverse drug reactions.

There are several mechanisms that can cause accumulation of drugs. The first one is inhibition: a drug can diminish the expression of a CYP gene. That causes a gene to produce less enzyme. Less enzyme means less capability of metabolizing the substrate, in this case a drug.

The second mechanism that can cause drug accumulation is substrate competition. With a limited amount of CYP enzyme, having two or more substrates may mean that neither get metabolized effectively, and both drugs might accumulate in the body. The third mechanism is when a CYP gene produces a CYP enzyme that is not working properly, that is, the alleles have reduced metabolic ability. The first two are drug-drug interactions. The third one causes drug-gene interactions. I will give examples of all three.

Patients are seldom put on just one drug. One medication (A) can influence the function of a CYP gene, e.g. slow down the expression of that P450 enzyme. This can happen even if that drug does not need that CYP to be metabolized. This is called “inhibition,” see table 1:

Table 1: Citalopram metabolized by CYPs

Citalopram is metabolized, used as what is called a substrate (S), by CYP2C19, CYP2D6 and CYP3A4. It inhibits (Inh) CYP1A2, CYP2C19, and CYP2D6.

But if another medication (B) is metabolized by one of those CYPs that are inhibited, then drug B could accumulate in the body (see table 2). The interactions shown in color indicate the danger of side effects — the darker the color, the bigger the chances of adverse drug reactions.

Table 2: Drug-drug interactions

Naproxen is metabolized by CYP1A2, but because citalopram inhibits CYP1A2, the levels of naproxen could rise, increasing the chances of side effects.

Another form of drug-drug interaction is when two drugs need the same CYP to be metabolized (see table 3).

Table 3: Drug-drug interactions

In this example, Remeron is combined with clonidine. Both drugs are metabolized by CYP1A2. Thus, there is substrate competition for this CYP enzyme. This means that the levels of both drugs could rise.

For CYP2D6, there is substrate competition as well, and, at low levels of Remeron, this CYP will be inhibited. As the drug levels rise, Remeron will stimulate the production of this CYP (Ind = induction). That will not be of much help, since the competition between the two drugs will slow down the metabolic rate of the drugs anyway. For CYP3A4, the situation could be worse: there is competition between the two drugs and Remeron inhibits CYP3A4. The metabolism of both drugs could be significantly reduced.

These drug-drug interactions can be extremely dangerous, even if the CYPs are genetically normal. In a 2006 study in older patients, the mean number of medications was 8.1 with a standard deviation of 2.5. Reducing the number of drugs by two decreased the mortality rate significantly. This is no exception. It is easy to see why medication use is now the third leading cause of death.

This picture becomes even more grim if we take into account drug-gene interactions. If drug-drug interactions, by themselves, are hazardous, they are even more so when CYPs (which are supposed to get rid of the drugs) are not working properly. It has been estimated that around 99% of individuals have one or more variant alleles that could influence the enzymes that metabolize drugs. Most prescribers and patients are not aware of this. If doctors prescribe drugs assuming the patients have no problems metabolizing these medications, they jeopardize the health of their patients. Those people with problems metabolizing — the vast majority of patients — are at great risk of side effects.

Let us look at the example again in which citalopram is combined with naproxen. But now, through DNA testing, we have discovered that the individual has some loss of function alleles, so he or she is an Intermediate Metabolizer. In this case, the CYP genes for which there is loss of function alleles are colored in red.

Table 4: Drug-gene interactions

Let’s look at CYP1A2 in table 4. This CYP has only one functioning allele, which is inhibited by citalopram. The function of this CYP will likely be diminished to such a degree that the person will convert from an Intermediate Metabolizer into a Poor Metabolizer. For CYP2D6 and CYP3A4, similar problems arise concerning Citalopram. With two out of three designated CYPs practically nonfunctional, this patient will be depending on CYP2C19 to eliminate Citalopram. With so much loss of function, the levels of Citalopram will likely rise and cause toxicity.

Citalopram is strongly associated with violence. This patient is put at great risk by their doctor prescribing this medication to someone who is basically a Poor Metabolizer for the CYPs necessary to expel that drug from the body. Drugs that are metabolized by CYPs for which patients are Poor Metabolizers should not be prescribed. Poor metabolizers can hardly metabolize drugs, so side effects are expected.

Other prescriptions for disaster for people with variant CYP alleles are combinations like Cymbalta and Xanax.

Table 5: Drug-gene interactions

Cymbalta is metabolized by CYP1A2. If the individual has one loss of function allele, CYP1A2 will not metabolize Cymbalta at a normal rate. CYP2D6 can also metabolize Cymbalta. Unfortunately, this individual has one loss of function allele for this gene. In addition, Cymbalta will inhibit its own metabolism. If the normal enzymes are limited in metabolizing their usual substrates, CYP3A4 is the backup system. In this case, that will not be very helpful. There is an additional loss of function allele for CYP3A4, and Xanax is a competing substrate. These are simple interactions, but they are responsible for many side effects, which can result in death.

CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 metabolize more than 90% of medication. Generating a DNA profile of these CYPs will provide the physician with valuable information. It is a fact that doctors can spend only so much time with a patient. To assist prescribers, there are drug interaction databases available online to screen drug-drug and drug-gene interactions — for example, the Pharmacogenomics Knowledge Base https://www.pharmgkb.org/index.jsp and Transformer SuperCyp http://bioinformatics.charite.de/transformer/.

Within minutes, a doctor can get a clear indication whether the medication he or she is about to prescribe can be a danger to the patient. If those extra minutes can save a patient’s life, they are well spent.

Other enzymes are also involved in metabolizing psychotropic medication, and other medication besides antidepressants, antipsychotics, tranquilizers, mood stabilizers, AHDH medication, etc. can cause acts of violence. For example, Varenicline (Chantix®) as an aid to quit smoking, isotretinoin (Absorica®, Accutane®, Amnesteem®, Claravis®, Myorisan®, Sotret®, and Zenatane™) against acne, oxycodone against pain, or interferon alfa to regulate the immune system.

These drugs are not primarily prescribed to patients with social, psychological or psychiatric problems. The argument that violence is caused by an underlying psychiatric disorder has been proven wrong repeatedly (see papers by Bielefeld and Maund and their colleagues at the Cochrane Collaboration) , and also the blog by Peter Gøtzsche from November 16, 2016).

The technology for genotyping these five CYPs is widely available and would cover most of these dangerous drugs. I am convinced that once doctors start realizing that they are responsible for senseless suffering and that there is a way to, at least, diminish the chances of such horrific side effects as suicide and homicide by a simple DNA test, they will fully embrace “personalized medicine.”