5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression

Illi, Ari; Setälä-Soikkeli, Eija; Viikki, Merja; Poutanen, Outi; Mononen, Nina; Lehtimäki, Terho; Leìnonen, Esa; Kampman, Olli

doi:10.1097/wnr.0b013e32832eb708

Cited by 106 publications

(83 citation statements)

References 16 publications

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“…Indeed, rs7333412, rs7324017, rs1923882 and rs7997012 (Peters et al 2009) are located in this region and were associated with antidepressant response in the STAR*D sample. Several other studies investigated rs7997012 with negative results (Illi et al 2009;Kishi et al 2009;Perlis et al 2009;Uher et al 2009;Horstmann et al 2010), although none of these included samples as large as the STAR*D study. The effect of rs7997012 and rs6313 on antidepressant efficacy was confirmed by the most recent meta-analysis (Lin et al 2014).…”

Section: Genetic Polymorphisms Different Polymorphismsmentioning

confidence: 99%

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Fabbri

Hosák

Mößner

et al. 2016

The World Journal of Biological Psychiatry

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Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under-or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in anti-depressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-a receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

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Section: Genetic Polymorphisms Different Polymorphismsmentioning

confidence: 99%

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Fabbri

Hosák

Mößner

et al. 2016

The World Journal of Biological Psychiatry

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“…33,66,86 We noted that subsets of mice from both genotypes were responsive to SSRIs in the TST and some were not responsive. Human subjects given SSRIs in clinical studies are frequently classified as responders and non-responders [37][38][39]96 as are mice treated with antidepressants in behavioral tests, 40,86 so we followed this convention presently. Data from SSRI treatment of wild-type and TPH2−/− groups of mice was re-examined and classified mice in either group as drug responders if their immobility times were 2 standard deviations lower than the mean of their respective non-treated controls.…”

Section: Treatment Of Mice With Ssrismentioning

confidence: 99%

“…5A-C), we noted that some individual TPH2−/− mice clearly displayed substantial reductions after drug treatment. Depressed patients treated in clinical trials with SSRIs are commonly classified as responders and non-responders, [37][38][39] generally based on a pre-determined reduction in depression scores (e.g., usually 50%). The concept of responsive and non-responsive subjects has also been recognized in animal models of antidepressant-resistance.…”

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confidence: 99%

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Angoa‐Pérez

Kane

Briggs

et al. 2014

ACS Chem. Neurosci.

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Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Serotonin selective reuptake inhibitors (SSRIs) are the most common treatment for depression and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and ratelimiting enzyme in the biosynthetic pathway of 5HT in the CNS and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their anti-depressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2 −/− mice on the sucrose preference test, tail suspension test and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2−/− mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2 −/− mouse questions the role of 5HT in depression. Furthermore, the TPH2 −/− mouse may Detroit, MI 48201-1916. Phone: 313-476-4457, Fax: 313-576-1112. donald.kuhn@wayne.edu. Author Contributions MAP, MJK, DIB, NHM and CES conducted the in vivo behavioral and pharmacological experiments. DMF and MAP conducted the in vitro synaptosomal 5HT uptake experiments. MAP, MJK and DMK interpreted the data. MAP, MJK and DMK conceived of project and wrote the paper. All authors edited and approved the final version of the manuscript. NotesThe authors declare no competing financial interest. SUPPORTING INFORMATION AVAILABLEThe numbers of TPH2+/+ and TPH2−/− mice classified as responders or non-responders (specified by sex) to the SSRIs fluoxetine, citalopram and paroxetine is included in SI Table 1. The immobility time cutoff values for defining whether a subject was classified as a responder or non-responder to SSRIs is presented in SI Table 2. Information on the specific stressors used in the UCMS is included in SI Table 3. This information is available free of charge via the Internet at http://pubs.acs.org. U.S. Department of Veterans Affairs VA Author ManuscriptVA Author Manuscript VA Author Manuscriptserve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system. Keywordsserotonin; TPH2; TPH2 knock out; depression-like behavior; SSRIs; SERT The serotonin (5HT) neuronal system innervates nearly the entire neuraxis from...

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“…Despite preliminary negative results [102], a subsequent study reported that C/T carriers showed better AD response [103]. Nevertheless, this finding was not replicated by further studies [82,104].…”

Section: Serotonin Receptorsmentioning

confidence: 52%

Pharmacogenetics of antidepressant drugs: An update

Crisafulli¹,

Drago²,

Calabrò³

et al. 2014

Hosp Pharm Int Multi J

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SUMMARYPharmacological treatment of depressive disorders is characterized by poor predictability of individual response. In recent years, the increasing evidence has demonstrated that genetic factors play a critical role in determining the differences in treatment outcome to antidepressant drugs. A number of pharmacogenetic studies on antidepressant drugs has been conducted, and genetic variations at level of drug metabolizing enzymes, drug transporters and drug targets, possibly influencing the clinical response, have been identified. Pharmacogenetics may hopefully provide the basis for individualized pharmacotherapy of depressive disorders in order to maximize the probability of a favorable response and minimize the risk of adverse drug reactions. In this article, the major findings related to the pharmacogenetics of genes involved in the pharmacokinetics and pharmacodynamics of antidepressant drugs are critically reviewed.

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5-HTR1A, 5-HTR2A, 5-HTR6, TPH1 and TPH2 polymorphisms and major depression

Cited by 106 publications

References 16 publications

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

Pharmacogenetics of antidepressant drugs: An update

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