Treatment Outcomes of Depression

Mrazek, David A.; Biernacka, Joanna M.; McAlpine, Donald E.; Benitez, Joachim; Karpyak, Victor M.; Williams, Mark D.; Hall‐Flavin, Daniel K.; Netzel, Pamela J.; Passov, Victoria; Rohland, Barbara M.; Shinozaki, Gen; Hoberg, Astrid A.; Snyder, Karen; Drews, Maureen S.; Skime, Michelle; Sagen, Jessica; Schaid, Daniel J.; Weinshilboum, Richard M.; Katzelnick, David J.

doi:10.1097/jcp.0000000000000099

Cited by 43 publications

(24 citation statements)

References 14 publications

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“…The sample comprised 240 MDD participants from the Mayo Clinic NIH-Pharmacogenomics Research Network - Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) (Mrazek et al, 2014). Participant selection, symptomatic evaluation, and blood sample collection for the PGRN-AMPS clinical trial have been described in our previous work (Gupta et al, 2016; Ji et al, 2014; Mrazek et al, 2014; Schiepers, Wichers, & Maes, 2005). MDD symptoms were assessed using the HRSD 17 at baseline and after eight weeks of treatment with citalopram or escitalopram.…”

Section: Methodsmentioning

confidence: 99%

Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes

Ahmed¹,

MahmoudianDehkordi

Bhattacharyya

et al. 2019

Preprint

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Edward Craighead, PhD provided funding to treat non-remitters to the first treatment with combination medication and psychotherapy, to allow follow-up of patients for up to two years to identify predictors of recurrence, and to add patients to the sample to adequately power these studies. Additional support was received from PHS Grant UL1 Abstract Background: Acylcarnitines have important functions in mitochondrial energetics and β oxidation, and have been implicated to play a significant role in metabolic functions of the brain.This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD)-(core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+))-following treatment with a selective serotonin reuptake inhibitor (SSRI). Methods:Depressed outpatients (n=240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and eight weeks post-treatment were profiled for multiple-, short-, medium-and longchain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminate the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differ between groups. Results: At baseline, significantly lower concentrations of short-and long-chain acylcarnitines were found in CD+ and NVSM+ compared to ANX+, and the shortchain acylcarnitines remained lower after eight weeks. At eight weeks, the medium-and longchain acylcarnitines were significantly lower in NVSM+ compared to ANX+. Regarding changes baseline to week eight, short-chain acylcarnitine levels significantly increased in CD+ and ANX+, and medium-and long-chain acylcarnitines significantly decreased in NVSM+ and CD+. Conclusions: In depressed patients treated with SSRIs, β -oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics. 7

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Section: Methodsmentioning

confidence: 99%

Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes

Ahmed¹,

MahmoudianDehkordi

Bhattacharyya

et al. 2019

Preprint

Self Cite

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“…11, 36, 37 Plasma metabolite concentrations were assayed using samples from 306 randomly selected MDD patients at baseline and after four and eight weeks of SSRI therapy using a high-performance liquid chromatography electrochemical coulometric array (LCECA) metabolomics platform. 31, 39 See Supplementary Text for details.…”

Section: Methodsmentioning

confidence: 99%

TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics

et al. 2016

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Millions of patients suffer from Major Depressive Disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, four and eight weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (p<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (p<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (p=7.84E-09) SNP clusters on chromosome four 5’ of TSPAN5 and a cluster across ERICH3 on chromosome one (p=9.28E-08) that were also observed during GWAS for change in serotonin at four (p=5.6E-08 and p=7.54E-07, respectively) and eight weeks (p=1.25E-06 and p=3.99E-07, respectively). The SNPs on chromosome four were eQTLs for TSPAN5. Knockdown (KD) and over expression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may play a role in SSRI treatment outcomes.

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“…SNPs with the smallest P -values in each of the top 10 association regions in the two primary analyses (that is, top SNP in each region) were tested for association with equivalent outcomes in two independent samples: the PGRN-AMPS 15 and STAR*D. 14 GWA analyses utilizing these two samples are published, 5 , 7 and both data sets are available through controlled access via the database for Genotypes and Phenotypes (dbGaP; http://www.ncbi.nlm.nih.gov/gap ).…”

Section: Methodsmentioning

confidence: 99%

“…This is the first report of findings from a GWAS of SSRI treatment response based on the ISPC sample. Data from two prior GWAS of SSRI response, the Mayo Clinic Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) 7 , 15 and the STAR*D study, 14 were used for replication analysis, and a meta-analysis of the three studies was performed.…”

Section: Introductionmentioning

confidence: 99%

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

et al. 2015

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Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

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Treatment Outcomes of Depression

Cited by 43 publications

References 14 publications

Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes

Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes

TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics

The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

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