Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure

Milosavljević, F.; Bukvić, N.; Pavlović, Zorana; Miljević, Čedo; Pešić, Vesna; Molden, Espen; Ingelman‐Sundberg, Magnus; Leucht, Stefan; Jukić, Marin M.

doi:10.1001/jamapsychiatry.2020.3643

Cited by 121 publications

(120 citation statements)

References 141 publications

(365 reference statements)

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“…Nevertheless, our large-scale data-driven approach-like recent human genetic (36-52) and neuroimaging (57-59) antidepressant treatment studieshave revealed novel insights into the relationship between chronic pain and depression. Along with animal model and human pharmacogenetic studies (53-56, 116,117,[121][122][123][124][125], there is also independent converging evidence for the critical role of subcortical brain regions in mediating pain and mood (126). The application of rigorous statistical genetics methodologies to large-scale neuroimaging data, for example, has already produced several major discoveries, such as advancing our understanding of causal pathways (subcortical), brain networks and medication response markers in mood disorders (127)(128)(129)(130)(131)(132)(133).…”

Section: Discussionmentioning

confidence: 99%

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

et al. 2021

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The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for their comorbidity in the Australian Genetics of Depression cohort study (N = 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 [1.37–2.54]), recent suicide attempt (OR = 1.88 [1.14–3.09]), higher use of tobacco (OR = 1.05 [1.02–1.09]) and misuse of painkillers (e.g., opioids; OR = 1.31 [1.06–1.62]). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 [0.68–0.83]), escitalopram (OR = 0.75 [0.67–0.85]) and venlafaxine (OR = 0.78 [0.68–0.88]) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 [0.30–0.67]), escitalopram (OR = 0.45 [0.27–0.74]) and citalopram (OR = 0.32 [0.15–0.67]) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.

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Section: Discussionmentioning

confidence: 99%

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

et al. 2021

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“…Indeed, the role of genetic variants in drug-metabolizing genes (pharmacogenetics) is well established and is highly relevant for variable responses and even toxic outcomes in the treatment of pain and depression. [86][87][88][89][90][91] Genetic variant evaluation is a powerful tool since it can direct the analyst to specific mechanisms in the body that are likely to be dysfunctional under injury or stress, and other systems that are likely to be normal. 92 These tools are therefore most useful early in the course of disease before the damage of poorly managed pathogenic pathways becomes irreversible.…”

Section: Cp As a Complex Gene-environment-metabolic Diseasementioning

confidence: 99%

Severe Pain in Chronic Pancreatitis Patients: Considering Mental Health and Associated Genetic Factors

Dunbar¹,

Saloman²,

Phillips³

et al. 2021

JPR

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Pain is the most distressing and disruptive feature of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) resulting in low quality of life (QOL) and disabilities. There is no single, characteristic pain pattern in patients with RAP and CP. Abdominal imaging features of CP accurately reflect morphologic features but they do not correlate with pain. Pain is the major driver of poor quality of life (QOL) and it is the constant pain, rather than intermittent pain that drives poor QOL. Furthermore, the most severe constant pain experience in CP is also a complex condition. The ability to target the etiopathogenesis of severe pain requires new methods to detect the exact pain mechanisms in an individual at cellular, tissue, system and psychiatric levels. In patients with complex and severe disease, it is likely that multiple overlapping mechanisms are simultaneously driving pain, anxiety and depression. Quantitative sensory testing (QST) shows promise in detecting alterations in central processing of pain signals and to classify patients for mechanistic and therapeutic studies. New genetic research suggests that genetic loci for severe pain in CP overlap with genetic loci for depression and other psychiatric disorders, providing additional insights and therapeutic targets for individual patients with severe CP pain. Well-designed clinical trials that integrate clinical features, QST, genetics and psychological assessments with targeted treatment and assessment of responses are required for a quantum leap forward. A better understanding of the context and mechanisms contributing to severe pain experiences in individual patients is predicted to lead to better therapies and quality of life.

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“…Recently, a comprehensive review was published by Milosavljevic et al Compared with the CYP2D6 EM group, significant but marginal increases in racemic VEN were observed in the intermediate (IM) plus PM group (8 studies; 716 patients), although the number of studies was not enough to determine this conclusion. However, this study did not analyse enantiomer of VEN 21 . Further pharmacokinetic studies regarding enantiomers of VEN are required to perform a meta‐analysis of the association between enantiomers of VEN and CYP2D6 polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

CYP2D610* polymorphism and the enantioselective O‐desmethylation of S‐(+)‐ and R‐(‐)‐venlafaxine in Japanese psychiatric patients

Sasaki

Yasui‐Furukori

Komahashi‐Sasaki

et al. 2021

Basic Clin Pharma Tox

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According to previous studies, R‐(‐)‐venlafaxine (VEN) has higher enantioselectivity than S‐(+)‐VEN, and the plasma concentration of R‐(‐)‐VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady‐state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O‐desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S‐(+)‐VEN were approximately 1.9‐fold higher than those of R‐(‐)‐VEN. The plasma concentrations of S‐(+)‐VEN and R‐(‐)‐VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S‐(+)‐VEN and R‐(‐)‐VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R‐(‐)‐ODV/R‐(‐)‐VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R‐(‐)‐VEN and S‐(+)‐VEN. Further studies are needed to examine how these findings affect clinical practice.

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Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure

Cited by 121 publications

References 141 publications

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

Severe Pain in Chronic Pancreatitis Patients: Considering Mental Health and Associated Genetic Factors

CYP2D610* polymorphism and the enantioselective O‐desmethylation of S‐(+)‐ and R‐(‐)‐venlafaxine in Japanese psychiatric patients

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Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure

Cited by 121 publications

References 141 publications

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

Comorbid Chronic Pain and Depression: Shared Risk Factors and Differential Antidepressant Effectiveness

Severe Pain in Chronic Pancreatitis Patients: Considering Mental Health and Associated Genetic Factors

CYP2D6*10 polymorphism and the enantioselective O‐desmethylation of S‐(+)‐ and R‐(‐)‐venlafaxine in Japanese psychiatric patients

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CYP2D610* polymorphism and the enantioselective O‐desmethylation of S‐(+)‐ and R‐(‐)‐venlafaxine in Japanese psychiatric patients