Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder

Abstract

ImportanceEvidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects.ObjectiveTo determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD).Design, Setting, and ParticipantsThis randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications.InterventionIn the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage.Main Outcomes and MeasuresThe primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores).ResultsOf 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT.Conclusions and RelevanceIn this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD.Trial RegistrationClinicalTrials.gov Identifier: NCT03548675

A review of real-world evidence on preemptive pharmacogenomic testing for preventing adverse drug reactions: a reality for future health care

“…A 12-week, double-blind, parallel, multicenter randomized controlled trial by Pérez et al in 316 adult patients with major depressive disorder (MDD) evaluated the effectiveness of preemptive PGx testing-guided therapy over treatment as usual (TAU) and revealed that, in addition to significant improvement in treatment response, the burden of side effects was significantly reduced at 12 weeks in the PGx-guided treatment group [ 36 ]. In another multicentre randomized clinical trial in the Netherlands, Vos, Cornelis et al compared preemptive PGx informed treatment (PIT) with usual treatment among 111 patients with depressive disorders and reported that patients in the PIT group experienced fewer severe adverse effects than patients in the usual treatment group with faster attainment of therapeutic plasma concentrations [ 37 ].…”

Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study

“…However, it is unclear whether similar results can be achieved for other AD groups with less clear concentration-effect/side effect relationships. Furthermore, no significant reduction was seen in depressive symptoms [ 52 ]. With regard to the latter, a meta-analysis of five RCTs examining the effect of PGx-guided therapy on remission of depressive symptoms, showed that PGx-guided therapy with ADs had a positive effect on the likelihood of achieving remission in depressive symptoms.…”

Drug-Gene Risk Stratification in Patients with Suspected Drug-Induced Interstitial Lung Disease

“…An increasing number of pharmacogenetic studies have indicated that genetic testing prior to treatment may be useful either for setting the individual dose or for making the decision to use a particular drug [ 17 , 32 , 33 ] as well as for reducing clinically relevant ARDs by pre-emptive pharmacogenetic testing [ 34 , 35 ]. The era of very successful blockbuster drugs, the profitable ‘one-size-fits-all drugs’, is clearly declining [ 31 , 36 ].…”