Pharmacogenomics in Psychiatry

■ Virtually ALL OF US carry a clinically relevant variant of one or more pharmaco-genes.

■ The PK, PD, and HLA genetic variants are associated with variability in drug response.

■ In mental health, evidence supports the use of PGx testing for only 4 genes: CYP2C19, CYP2D6, HLA-B*15:02, and HLA-A*31:01

Pharmacogenomics in Psychiatry

Michelle was fighting tears from the moment we said hi.

She was referred to see me due to two failed antidepressant trials.

Pharmacogenetic test and consult were ordered to shed some light on why and to give direction for a better drug for her.

I braced for her story. I knew it well. It is the one shared by so many.

Through tears she explained life stressors, including her teenage daughter’s recent diagnosed of a mental health disorder.

Her guilt was palpable “I passed those genes to her, didn’t I?”

…

We talked genes, drugs, strategies.

Busted myths and powered her with education.

Through shared decision making with her and her provider, we selected a drug to better fit her needs.

…

When I saw her in a 6 week-follow up, Michelle was smiling. Eyes too.

“First time in months” she said.

Her daughter also did PGx testing and was prescribed the same drug.

“My kid is back!” she said.

…

Considering mental health crisis in the US, shouldn’t everyone who needs a medication, get PGx?

Well, It is complicated. The short answer: it is not a standard of care.

Yet.

Why mental health matters?

Mental health is fundamental to our health and wellness. It directly influences how we relate to self and one another.

Mental health disorders are common, complex to diagnose, and costly to treat. Many suffer quietly or may not recognize symptoms. One in five U.S adults do not have good mental health (according to the National Alliance on Mental Health Illness).

Depression affects 280 million people worldwide. The US spends around 200 billion yearly treating mental disorders, of which $70 billion for treating depression.

Drugs are the main treatment for most mental health disorders. Evidence based guidelines help providers chose the first line therapy.

But not everyone gets the same benefits. People respond differently to drugs. The same drug and dose given to one person may not work for another, or it may cause side effects severe enough to stop the treatment.

This is a trial-and-error model. The reason it’s still used is the lack of reliable biological markers of disease and treatment stratification. Not every depression looks the same. Therefore, the treatment should not be the same either.

PGx as a tool of Precision Psychiatry (yes, this is a real term)

We have known for decades that genetics played role, but only recently are we understanding how.

Pharmacogenomics studies how genetics affect drug response among people. Individualizing therapy based on responders (good tolerance and efficacy) vs non responders (poor tolerance and efficacy) is the focus of an emerging field of Precision Psychiatry.

The field is fueled by the advances in artificial intelligence that combine pharmacology, genetics, and psychiatry for greater precision in diagnosis and treatment.

Why is inheritance important to drug response?

Depending on the drug, genetic factors are estimated to account for 20–95% of the variability observed in drug disposition and effects. Genetics contributes to at least a quarter of total drug response variability across the population.

In PGx, biomarkers refer to pharmaco-genes or genes that encode for proteins involved in drug metabolism (pharmacokinetics or PK), drug receptor interactions (pharmacodynamic or PD), and drug hypersensitivity reactions (human leukocyte antigen or HLA).

Their genetic variants contribute to interindividual differences in drug response.

PGx used in psychiatry practice is mostly concerned with germline (inherited) mutations.

Psychotropic drugs have a large number of PGx biomarkers listed in their drug labels (n > 35), second only to oncology drugs.

Pharmacogenomics (PGx) studies how germline (i.e., inherited) mutations affect response to drugs.

How prevalent are genetic variants?

Genetic variants in pharmaco-genes are quite common and affect most of the population. For example, a study by the Mayo Clinic sequenced the DNA of over 10,000 patients, focusing on 12 clinically relevant pharmaco-genes.

Virtually all participants in the study (99.4%) had variants on at least 1 gene, including those that determine metabolism of drugs used for management of mental health disorders.

How do we test them genetic variants?

Easy: through PGx test panels.

What is not easy is lack of standardization between them.

There are many clinical labs that do PGx testing (wet labs). They also may offer their proprietary algorithms (dry labs).

Most panels focus on drugs in psychiatry and genes related to them (CYP2C19, CYP2D6, etc).

But, many include genes with limited evidence or no guidance from CPIC or FDA; these include COMT, CYP1A2, CYP2B6, CYP3A4, DRD2, HTR2A, HTR2C, MTHFR, SLC64A, and UGT2B15.

PGx testing laboratories may assess loss or gain of functional alleles and report more established and common variants in pharmacokinetic genes such as CYPs.

These alleles are reported as a genotype (in the form of *2, *41, *4+*68, etc.) with corresponding enzyme activity or phenotype, which is not standardized across clinical laboratories. Yikes!

Phenotypes are typically bucketed in 5 categories: poor metabolizer or PM (i.e., no to little activity), intermediate metabolizer or IM (reduced activity), extensive/normal metabolizer or NM (normal activity), rapid metabolizer or RM (increased activity), and ultrarapid metabolizer or UR (greatly increased activity).

Activity scores (AS), as an alternative, have been used in an effort to standardize genotype-to-phenotype classifications especially for a complex gene such as CYP2D6.

Recently, a consensus was reached among international panels of CYP2D6 experts to use the AS system over the older system to minimize discrepant CYP2D6 results.

What about the evidence and guidelines?

In mental health, the current evidence supports only 4 genes as clinically actionable: CYP2D6, CYP2C19, HLA-A*31:01, and HLA-B*15:02 as reflected in the CPIC guidelines and prescribing recommendations for several psychotropic drugs.

For specifics drug-gene pairs, additional insights, and references, you can check our a CE publication I wrote for Pharmacy Today here: https://www.pharmacist.com/Publications/Pharmacy-Today/Article/pharmacogenomics-in-treating-mental-health-disorders