Genetics enables personalized dosing of antidepressants Individually determined rate of drug degradation plays important role

How quickly patients break down antidepressants depends heavily on the genetic code of the CYP450 enzymes they’ve inherited. If the genetically determined degradation rate is known, the dosage of antidepressants (TCAs) can be based upon it, researchers from the Radboudumc and their Dutch colleagues write in a paper in JAMA Network Open. That way, patients would receive an optimal dose against depression almost a week earlier, compared with the current approach.

Patients with severe depression are often treated with tricyclic antidepressants (TCAs) if an initial antidepressant is ineffective. TCAs increase the availability of neurotransmitters (serotonin and norepinephrine) in the brain, reducing depressive symptoms in many patients. But the treatment also has drawbacks. For example, it takes several weeks to find the right dosage. In addition, the medication often causes side effects such as a dry mouth, gastrointestinal symptoms, weight gain, confusion or sexual problems.

Breakdown rate
TCAs (such as nortriptyline, clomipramine and imipramine) are the oldest group of medications for depression. An advantage of this group of antidepressants is that the concentration in the blood at which efficacy is optimal is known; it’s called the therapeutic plasma concentration. "Interestingly," says Joost Janzing, psychiatrist at the Radboudumc, "this concentration is largely dependent on the rate at which the drug is broken down in the body. In that breakdown, the enzyme cytochrome P450 plays a major role. There are several enzyme types, such as CYP2D6 and CYP2C19, each of which can have variations in its genetic code. And depending on that genetic code, that enzyme ends up working tremendously hard, normally or just a little bit."

Personal profile
With this knowledge, the drug degradation rate in each individual patient can be determined in advance. If you know the genetic code, then you can adjust the dosage of TCAs accordingly. "In principle, you could reach the right therapeutic plasma concentration faster," says psychiatrist and first author of the article Niels Vos, "and that is exactly what we have been investigating in recent years. In our study, we examined for the first time in clinical practice the guidelines for adjusted dosing of tricyclic antidepressants established by the Pharmacogenetics Working Group in the KNMP. Just now we’ve published the results in a paper in JAMA Network Open."
In the Radboudumc, Erasmus MC, Catharina Hospital and Pro Persona, 111 patients eventually participated in the randomized study; 55 patients received the usual TCA treatment and 56 patients followed a TCA treatment based on their personal ‘cytochrome profile’. Overall, the faster the patient's medication degrades, the higher the drug dose must be to compensate the accelerated degradation.

Pharmacogenetics makes sense
The study shows the pharmacogenetic approach is paying off in this case. Janzing: "With the usual treatment, you reach the right therapeutic concentration in the blood after an average of 22 days. With the pharmacogenetic approach, we reached this after only 17 days, a decrease of over 22 percent. The effect on depression is similar in both groups, but there was also a faster decrease in side effects.
Use of pharmacogenetics has long been mentioned as a method by which patient treatment can be optimized. Yet in actual practice it’s still used only to a limited extent. Janzing: "In part this is due to the lack of well-executed randomized studies comparing the pharmacogenetic approach with standard treatment. This study shows that TCA dosing for the individual patient based on pharmacogenetics can be done safely and can be meaningful as well."
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Paper in JAMA Network Open: Effectiveness of Genotype-specific Tricyclic Antidepressant Dosing in Patients with Major Depressive Disorder: A Randomized Clinical Trial - Cornelis F. Vos, Sophie E. ter Hark, Arnt F.A. Schellekens, Jan Spijker, Annemarie van der Meij, Anne J. Grotenhuis, Raluca Mihaescu, Wietske Kievit, Rogier Donders, Rob E. Aarnoutse, Marieke J.H. Coenen, Joost G.E. Janzing

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