Pharmacogenetics in Depression

Pharmacogenetics is the study of how individual genetic variations influence drug response. In psychiatry, and particularly in the treatment of major depressive disorder, this field is emerging as a valuable tool to personalize the selection and dosing of antidepressants, with the aim of enhancing therapeutic efficacy and minimizing the risk of adverse effects.

Despite the availability of numerous antidepressants, clinical response remains unpredictable: approximately one in three patients fails to achieve satisfactory remission with the first-line treatment. The integration of pharmacogenetic testing into clinical practice may represent a breakthrough toward precision psychiatry.

Key Genes Involved

Current pharmacogenetic tests focus on two main areas:

• Metabolic enzymes (primarily within the cytochrome P450 system);
• Neurotransmitter receptors and transporters involved in the pharmacodynamics of antidepressants.

Metabolism: The CYP450 System

The cytochrome P450 family consists of hepatic enzymes responsible for the metabolism of numerous psychotropic drugs. The most clinically relevant genetic polymorphisms include:

• CYP2D6: involved in the metabolism of many tricyclic antidepressants, SSRIs (e.g., paroxetine, fluoxetine), and antipsychotics;
• CYP2C19: metabolizes citalopram, escitalopram, sertraline, and amitriptyline.

Based on genetic profiling, individuals can be classified as:

• Poor metabolizers: at risk for toxicity due to drug accumulation;
• Intermediate metabolizers: partially reduced metabolic activity;
• Extensive (normal) metabolizers: normal drug metabolism;
• Ultrarapid metabolizers: at risk for treatment failure due to excessively rapid elimination.

Pharmacodynamics: Receptors and Transporters

Some tests analyze polymorphisms in genes that influence neurotransmitter sensitivity:

• SLC6A4 (serotonin transporter, 5-HTTLPR gene): associated with SSRI response;
• HTR2A (5-HT2A receptor): implicated in tolerability and response to serotonergic antidepressants;
• COMT (catechol-O-methyltransferase): affects dopamine and norepinephrine levels, with implications for mood regulation and cognitive response to antidepressants.

Indications and Limitations of Pharmacogenetics

According to international guidelines (e.g., CPIC, APA, CANMAT), pharmacogenetic testing is particularly useful in the following scenarios:

• Treatment-resistant depression following two or more adequate trials;
• Severe or unusual side effects at standard doses;
• Complex polypharmacy with a high risk of drug–drug interactions;
• Family history of atypical response or tolerability to antidepressants.

However, pharmacogenetics:

• Does not predict clinical response with certainty;
• Does not replace clinical judgment or dynamic therapeutic adjustment;
• Provides probabilistic insights that must be integrated with patient history, symptom profile, and preferences.

Available Tests and Clinical Interpretation

Most pharmacogenetic panels currently available simultaneously analyze polymorphisms in multiple metabolic and pharmacodynamic genes. Reports typically categorize medications into three groups:

• Medications to be used with caution or avoided (increased risk of toxicity or inefficacy);
• Medications with standard recommendation (favorable genetic profile);
• Medications requiring dose adjustment or close monitoring.

Therapeutic decisions based on test results should be made in collaboration with the patient, clearly explaining the benefits and predictive limitations, in order to maintain a person-centered approach.

References
1. Bousman CA et al. Pharmacogenetic tests and depressive symptom remission: a meta-analysis of randomized controlled trials. Pharmacogenomics. 2019;20(1):37–47.
2. Greden JF et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):909–917.
3. Thase ME et al. Clinical utility of pharmacogenetic testing in depression: a meta-analysis. Psychiatr Serv. 2020;71(10):960–973.
4. Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98(2):127–134.
5. Fabbri C et al. Clinical implementation of pharmacogenetics in psychiatry: current status and future perspectives. Pharmacogenomics J. 2020;20(4):462–471.
6. Jukić MM et al. Pharmacogenomics of antidepressant treatment. Curr Pharm Des. 2016;22(32):4956–4967.
7. Altar CA et al. Clinical validity of cytochrome P450 metabolism and serotonin gene variants in guiding treatment for major depressive disorder. Clin Psychopharmacol Neurosci. 2015;13(2):150–167.
8. Giacomini KM et al. The impact of pharmacogenetics on drug development and regulatory decision making: can we meet the challenges?. Clin Pharmacol Ther. 2017;101(5):610–612.
9. International Society of Psychiatric Genetics (ISPG). Genetic Testing Statement. 2019.
10. Bousman CA, Hopwood M. Commercial pharmacogenetic-based decision-support tools in psychiatry. Lancet Psychiatry. 2016;3(2):585–590.