Paucity of Evidence for Biomarkers of Tricyclic Antidepressant Treatment Response

Tricyclic Antidepressant
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Investigators searched publication databases through October 2021 for studies of drug-specific biomarkers for tricyclic antidepressant treatment response.

A systematic review found that biomarkers of treatment response to tricyclic antidepressants (TCAs) for major depressive disorder (MDD) were limited and did not have adequate replication. These findings were published in the Journal of Psychiatric Research.

Investigators from Radboud University in the Netherlands searched publication databases through October 2021 for studies of drug-specific biomarkers for TCA treatment response. A total of 20 studies of genetic markers and 18 studies of nongenetic markers were included in this review.

The enzymes cytochrome P450 family 2 subfamily D member 6 (CYP2D6) and cytochrome P450 family 2 subfamily C member 19 (CYP2C19) are involved in metabolism of TCAs. It is established that concentrations of TCA are influenced by polymorphisms of these enzymes, but their relationship with clinical response has not been clarified. In addition, 2 studies found no response between CYP2D6 genotypes and clomipramine or CYP2C19 genotypes and imipramine.

The solute carrier family 6 member 4 (SLC6A4) or serotonin transporter (SERT) and serotonin-transporter-linked promoter region (5-HTTLPR) have been linked with MDD and are targets of treatment. Studies of long and short 5-HTTLPR alleles found no difference in the reduction of depressive symptoms. However, a study conducted in Korea found a better response to nortriptyline among individuals who carried a specific polymorphism in the promoter region of 5-HTTLPR.

The gene brain-derived neurotrophic factor (BDNF) plays a role in neuronal plasticity and is associated with MDD. Some studies identified polymorphisms which associated with response to desipramine and nortriptyline; however, no associations survived the permutation test.

There are many indicators that inflammation is involved with the pathophysiology of mood disorders. However, multiple studies failed to find a relationship between various genetic and nongenetic markers of inflammation with MDD treatment response.

For nongenetic biomarkers, a study found a relationship between cortisol suppression and desipramine response; however, the relationship was not replicated in another study. A study published in 1995 observed high pre-treatment alpha 2A-adrenoceptor (A2A-AR) agonist affinity among responders to imipramine.

This review was limited by the fact that the majority of studies were published over 5 years ago.

“In conclusion, this review identified several potential drug-specific biomarkers, but replication of study results has not taken place. Despite the necessity for TCA treatment optimization due to high risk for adverse effects and a delayed onset of response, biomarker studies reporting drug-specific results for TCAs are still limited and robust replication studies are lacking,” stated the review authors.


ter Hark SE, Vos CF, Aarnoutse RE, Schene AH, Coenen MJH, Janzing JGE. Biomarkers as predictors of treatment response to tricyclic antidepressants in major depressive disorder: a systematic review. J Psychiatr Res. 2022;150:202-213. doi:10.1016/j.jpsychires.2022.03.057