Pharmacogenomics in treatment of depression and psychosis: an update

Jukić, Marin M.; Milosavljević, F.; Molden, Espen; Ingelman‐Sundberg, Magnus

doi:10.1016/j.tips.2022.09.011

Cited by 28 publications

(25 citation statements)

References 73 publications

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“…In addition, it is clear that clinical outcome is influenced by many other biological and nonbiological factors in addition to antidepressant plasma concentrations. 5,[34][35][36][37][38] 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.…”

Section: Main Findingsmentioning

confidence: 99%

“…As a result, the benefit of pharmacogenetics in clinical practice remains unknown. 4,5 Given the delayed onset of treatment response, high occurrence of nonresponse, and common adverse effects of antidepressants in the treatment of unipolar major depressive disorder (MDD), personalization of antidepressant pharmacotherapy is highly needed. [6][7][8] Antidepressants are metabolized by various isoforms of cytochrome P450 (CYP450) enzymes, notably the CYP450 2D6 (CYP2D6) and CYP450 2C19 (CYP2C19) isozymes.…”

Section: Introductionmentioning

confidence: 99%

“…To date, there is a lack of robust randomized clinical trials (RCTs) comparing pharmacogenetics-informed treatment (PIT) vs standard treatment. As a result, the benefit of pharmacogenetics in clinical practice remains unknown . Given the delayed onset of treatment response, high occurrence of nonresponse, and common adverse effects of antidepressants in the treatment of unipolar major depressive disorder (MDD), personalization of antidepressant pharmacotherapy is highly needed …”

Section: Introductionmentioning

confidence: 99%

“…Personalizing the dosage by taking CYP450 activity into account may result in earlier attainment of therapeutic plasma concentrations and consequently promote effectiveness and prevent adverse effects . A number of studies have found that pharmacogenetic testing is associated with higher effectiveness of antidepressants for the treatment of MDD . However, most of those studies did not provide information on the interaction between antidepressant and genotype because multiple genes are included in combinatorial pharmacogenetic tests.…”

Section: Introductionmentioning

confidence: 99%

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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: Main Findingsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2023

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“…It is known that the causes of psychiatric disorders are multifactorial, but also broadly genetically dependent (3,4), but the etiology for the different psychiatric disorders are largely unknown (5-7), and biomarkers can help with the understanding of the disorders' development. Thus, the field of psychiatry both regarding diagnostics and treatments is solely based on symptoms, which can lead to both under-and over-diagnosis, as well as ineffective treatments due to lack of knowledge in personal medicine (8)(9)(10). We believe and hope that in the near future, biomarkers will become an important part of psychiatry (2)(3)(4).…”

mentioning

confidence: 99%