Emerging Trends in Psychopharmacology

Greden et al. (2019) found that utilizing pharmacogenetic testing in the treatment of clients with psychiatric disorders potentially shortens remission times, improves long-term prognosis, improves changes in brain function and morphology, decreases the side effect burden for clients, and decreases the economic burden of the disease. Analyzing and understanding a client's genetic makeup and how an individual's genetics impact and affect pharmacological responses in the body allows healthcare providers to make more informed decisions about which medications are likely to be more effective than others, and it may also improve patient outcomes.

According to the NIH (2023), several federal agencies regulate genetic tests, including the Food and Drug Administration (FDA), the Centers for Medicare and Medicaid Services (CMS), and the Federal Trade Commission (FTC). Genomic testing is regulated on the following criteria: analytic validity, clinical validity, and clinical utility.

• Analytic validity- refers to how well the test consistently and accurately detects whether or not a specific genetic variant exists.
• Clinical validity- refers to how well the genetic variant(s) analyzed are conclusively shown to interact with a specific drug.
• Clinical utility- refers to whether the test can provide information about treatment management that will be helpful to patients and their providers.

According to the NIH (2023), CMS implements regulations to control the analytical validity of clinical genetic tests, but there is no federal oversight of the clinical validity of most genetic tests. The FDA has proposed new policies to enhance analytical validity regulation and expand oversight of the clinical validity of genetic tests. CMS draws on data from both the research and medical communities to determine the clinical utility of treatments and procedures.

Testing is indicated for clients with serious, persistent mental illnesses, including schizophrenia, bipolar disorder, and depression. Typically, a patient will have failed one or more medications prior to initiating pharmacogenomic testing. Not all medications have genetic markers, so considerations for augmenting or switching drugs and past medication trials are requested when performing the test. It is important to note that not all pharmacogenomic testing companies test for the same medications.

A client's DNA sample is collected by swabbing the inside of the cheek. No bloodwork or needles are involved. The sample is sent to a lab for analysis, and results are usually received within one to two weeks after collection. Depending on the company, a copy of the results is sent directly to the client once the ordering practitioner has reviewed them. A psychotropic report categorizes medications according to the level of gene-drug interactions.

Pharmacodynamic genes provide information about how a medication works on the body. Variations in these genes may affect the likelihood of response or risk of side effects with specific medications. Common pharmacodynamic genes tested include 5-hydroxytryptamine receptor 2A (HTR2A), opioid receptor mu 1 (OPRM1), adrenoceptor alpha 2A (ADRA2A), catechol-O-methyltransferase (COMT), and solute carrier family 6 member 4 (SLC6A4). Pharmacodynamic interactions occur when the effect of one drug is changed by the presence of another drug at its site of action. They compete for specific receptor sites or interfere with physiological systems (Palleria et al., 2013).

Pharmacokinetic genes provide information about how the body works on the medication. Variations in these genes may affect the metabolism of medication. Common pharmacokinetic genes tested include CYP with substrates of 1A2, 2B6, 2C19, 2C9, 2D6, and 3A4 (Crist, et al, 2018). CYP3A4 genes are the liver's most abundant subfamily of the CYP isoforms. More than 50% of all medications on the market today are impacted by the CYP3A4 system.

CYP3A4 activity is absent in newborns but reaches adult levels in the liver and small intestine at around one year of age. Pharmacokinetic interactions occur when one drug alters the rate or extent of absorption, distribution, metabolism, or elimination of another drug, resulting in diminished effects or drug potentiation (Palleria et al., 2013).

CYP450 is involved in breaking down chemicals and preventing them from building up to dangerous levels in the bloodstream (Freedman, 2019). Drug metabolism occurs in many sites in the body, including the liver, intestinal wall, lungs, kidneys, and plasma. However, the "liver is the primary site of drug metabolism and functions to detoxify and excrete xenobiotics (foreign drugs or chemicals) by enzymatically converting lipid-soluble compounds to more water-soluble compounds" (McDonnell & Dang, 2013, pp 264). Drug metabolism is achieved through phase I (oxidation, reduction, or hydrolysis of the parent drug), phase II (conjugation by coupling), or both. The most common phase I reaction is oxidation, catalyzed by the CYP system (McDonnell & Dang, 2013).

CYP pathways "are classified by family number (e.g., CYP1, CYP2) and a subfamily letter (e.g., CYP1A, CYP2D) and are then differentiated by a number for the isoform or individual enzyme (e.g., CYP1A1, CYP2D6). Drugs that share a common pathway have the potential for drug-drug interactions" (McDonnell & Dang, 2013, pp 266). Drugs with CYP activity may inhibit, induce, or be a substrate for a specific CYP enzymatic pathway and alter the metabolism of other drugs.

A drug that inhibits a CYP pathway of another drug may cause drug toxicity. Likewise, a drug that induces a CYP pathway may reduce the drug's concentration level, leading to subtherapeutic levels and treatment failure. Reviewing the most commonly prescribed drugs in the United States from 2022 shows that the majority of hepatically cleared drugs involved the CYP enzymes from families 1, 2, or 3, with the most common pathways involving CYP3A4/5, CYP2D6, and CYP2C19.

Many patients have medical comorbidities and require concomitant drug therapy, which increases the risk of drug-drug interactions. Understanding the CYP system for psychiatric medications and other disease-modifying agents is important to help reduce subtherapeutic responses and drug interactions. The inhibition of enzymes is a common role in drug action. Enzyme inhibitors block the binding site and prevent the binding of the substrate or can inhibit the enzyme's catalytic activity. Inhibition of CYP enzymes is the most common mechanism leading to drug-drug interactions (Deodhar et al., 2020).

According to Deodhar et al. (2020), the active site of an enzyme is the physical space where a molecule can bind to and create a reaction to convert the molecule to a metabolite (a substance necessary for metabolism). The allosteric site is a physical space or pocket separate from the active site. "Molecules can be allosteric activators or allosteric inhibitors, depending on how they influence enzyme activity. Drugs can bind to this site and change the structure of the enzyme” (Deodhar et al. 2020, pp. 3).

“Allosteric inhibitors may render the active site no longer accessible for substrate binding or make the site unable to catalyze reactions. Almost all cases of non-competitive inhibition are caused by allosteric regulation" (Deodhar et al. 2020, pp. 3). Drugs defined as inhibitors can bind to the active or the allosteric site of the enzyme. Inhibitors can be either substrates or non-substrates of the enzyme. Remember, non-substrate inhibitors typically bind to the allosteric site of the enzyme.

Inhibition leads to reduced metabolism of the substrate with an increase in the steady-state concentration of the drug. It potentiates the drug's effect and might lead to drug toxicity (Palleria et al., 2013). For example, both fluoxetine and paroxetine are strong CYP2D6 inhibitors. If either of these drugs is prescribed with a drug metabolized in the CYP2D6 pathway (e.g., risperidone), then the plasma concentrations of that drug (e.g., risperidone) will increase.

Another example would be a patient with high blood pressure on metoprolol (Lopressor), which utilizes the pharmacokinetic gene pathway via CYP2D6, being prescribed bupropion (used to treat depression). There would be a drug-drug interaction as both drugs compete for the same CYP450 active site (Deodhar et al., 2020); this is called competitive inhibition, as two substrates compete for the same active site. The drug with the stronger affinity will displace a weaker substrate from the active site and reduce the extent of its breakdown over time, allowing that drug to build up in the system, potentially causing toxicity and increased side effects. In this case, metoprolol is listed by the FDA as a moderately sensitive substrate for CYP2D6, and bupropion, a strong 2D6 inhibitor, will displace the moderately sensitive metoprolol. Thus plasma levels of metoprolol will increase (FDA, 2023).

Lakesha is a 45-year-old female with schizophrenia, reflux disease, hypothyroidism, hypertension, and diabetes. She is currently on metoprolol, levothyroxine, and omeprazole. She reports she recently started taking quinidine sulfate 300 mg twice daily after being prescribed it by her cardiologist for a new diagnosis of atrial fibrillation. She presents to the office for a follow-up appointment, reporting that although her hallucinations and paranoia are gone, she wants to quit taking quetiapine as it has been too sedating.

You discuss with Lakesha the benefits of pharmacogenomic testing and that her results are something she can take to every provider she sees going forward; the results will not change. Lakesha agrees to testing in the office today.

She later presents to the office for a follow-up appointment to get her pharmacogenomic test results. In reviewing the record, you find that she has failed on asenapine, cariprazine, and paliperidone (all metabolized through the CYP2D6 system) in the past. She completed pharmacogenetic testing, and her results indicate she is a poor metabolizer of the CYP2D6 and CYP3A4 substrates with normal CYP1A2 metabolism. As the practitioner caring for her today, you understand that drug-drug-gene interactions occur when the patient's CYP450 genotype and CYP450 inhibitors affect the individual's ability to clear a drug. You know that quetiapine is metabolized in the liver extensively. It is part of the CYP450 system with both 2D6 and 3A4 substrates. After reviewing her record, you realize that quinidine sulfate is also a strong CYP2D6 inhibitor and is likely increasing the blood levels of quetiapine, causing an increased side effect of sedation.

You review the available antipsychotics on the psychogenic results and see that thiothixene is primarily metabolized through the CYP1A2 substrate, for which the client is a normal metabolizer. You review the risks and benefits of switching from quetiapine to thiothixene. The client agrees to the medication change today.

✔ = Gene associated with medication metabolism, but predicted phenotype is normal.
X = Variation found that could impact metabolism

Julie has schizophrenia and severe anxiety. She is currently taking risperidone which is processed through the CYP2D6 pathway. The provider knows that strong CYP2D6 inhibitors will decrease the efficacy of any drug that requires transformation by CYP2D6 to its active metabolite. The patient tells the provider that she has done very well on paroxetine for her anxiety in the past and is requesting to restart this medication. The provider knows that paroxetine is a strong CYP2D6 inhibitor. If the patient wants to start paroxetine, the provider will need to adjust the dose of the risperidone as plasma concentrations of the risperidone will increase if paroxetine is prescribed.