Evaluating study designs and treatment outcomes of antidepressant pharmacogenetic clinical trials - Challenges and future perspectives. A critical review

Minelli, Alessandra; Barlati, Stefano

doi:10.1016/j.euroneuro.2022.04.007

Cited by 7 publications

(13 citation statements)

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“…Most previous studies 39 , 40 , 41 , 42 of treatment for MDD guided by pharmacogenetics examined the use of combinatorial pharmacogenetic tests (ie, multigene testing). Other studies 14 , 43 , 44 , 45 found promising results regarding remission rates; however, questions have been raised about whether the studies were properly randomized and blinded. 43 In most previous studies, 39 , 40 , 41 , 42 information was not presented regarding how the pharmacogenetic test results were translated into the choice for a specific antidepressant or antidepressant dosage as well as the extent to which the prescribers adhered to the dosing advice in their treatment strategy.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…Increasing the efficacy and accuracy in the choice of antidepressant treatment represents a major challenge as nonresponse or the development of side effects to a given drug may lead to discontinuation and non-adherence to therapy, resulting in increased social and health care costs due to the development of treatment-resistant depression or due to increased risk of relapse (4,10,35).…”

Section: Discussionmentioning

confidence: 99%

“…Symptomatic remission and maintenance of therapeutic effects over time are the primary goals of MDD treatment and the most common first-line therapeutic strategy for moderate to severe MDD is pharmacological: although different classes of antidepressants are currently available, the pharmacological approach to this disorder is commonly a process of trial and error, thus, it may (and often does) take several attempts to identify the optimal treatment for an individual patient (2)(3)(4). Approximately one third of patients achieve remission after the first therapeutic trial, whereas about another third develop a treatment-resistant form of depression (2,5,6).…”

Section: Introductionmentioning

confidence: 99%

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The role of pharmacogenetics in the treatment of major depressive disorder: a critical review

Barlati,

Minelli,

Nibbio

et al. 2023

Front. Psychiatry

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Pharmacological therapy represents one of the essential approaches to treatment of Major Depressive Disorder (MDD). However, currently available antidepressant medications show high rates of first-level treatment non-response, and several attempts are often required to find an effective molecule for a specific patient in clinical practice. In this context, pharmacogenetic analyses could represent a valuable tool to identify appropriate pharmacological treatment quickly and more effectively. However, the usefulness and the practical effectiveness of pharmacogenetic testing currently remains an object of scientific debate. The present narrative and critical review focuses on exploring the available evidence supporting the usefulness of pharmacogenetic testing for the treatment of MDD in clinical practice, highlighting both the points of strength and the limitations of the available studies and of currently used tests. Future research directions and suggestions to improve the quality of available evidence, as well as consideration on the potential use of pharmacogenetic tests in everyday clinical practice are also presented.

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“…Concurrent with the limited success of pharmacogenetic studies in predicting drug efficacy in mental disorders [ 26 , 27 ], a few studies have attempted to predict the efficacy of treatments using epigenetic profiles ( Tables S1–S3 ).…”

Section: Introductionmentioning

confidence: 99%

Can Epigenetics Predict Drug Efficiency in Mental Disorders?

David

Amir

Salalha

et al. 2023

Cells

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Psychiatric disorders affect millions of individuals and their families worldwide, and the costs to society are substantial and are expected to rise due to a lack of effective treatments. Personalized medicine—customized treatment tailored to the individual—offers a solution. Although most mental diseases are influenced by genetic and environmental factors, finding genetic biomarkers that predict treatment efficacy has been challenging. This review highlights the potential of epigenetics as a tool for predicting treatment efficacy and personalizing medicine for psychiatric disorders. We examine previous studies that have attempted to predict treatment efficacy through epigenetics, provide an experimental model, and note the potential challenges at each stage. While the field is still in its infancy, epigenetics holds promise as a predictive tool by examining individual patients’ epigenetic profiles in conjunction with other indicators. However, further research is needed, including additional studies, replication, validation, and application beyond clinical settings.

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Evaluating study designs and treatment outcomes of antidepressant pharmacogenetic clinical trials - Challenges and future perspectives. A critical review

Cited by 7 publications

References 31 publications

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

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

The role of pharmacogenetics in the treatment of major depressive disorder: a critical review

Can Epigenetics Predict Drug Efficiency in Mental Disorders?

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