Genomic Investigation of Remission and Relapse of Psychotic Depression Treated with Sertraline plus Olanzapine: The STOP-PD II Study

Introduction: Little is known regarding genetic factors associated with treatment outcome of psychotic depression. We explored genomic associations of remission and relapse of psychotic depression treated with pharmacotherapy. Methods: Genomic analyses were performed in 171 men and women aged 18–85 years with an episode of psychotic depression who participated in the Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). Participants were treated with open-label sertraline plus olanzapine for up to 12 weeks; those who achieved remission or near-remission and maintained it following 8 weeks of stabilization were eligible to participate in a 36-week randomized controlled trial that compared sertraline plus olanzapine with sertraline plus placebo in preventing relapse. Results: There were no genome-wide significant associations with either remission or relapse. However, at a suggestive threshold, SNP rs1026501 (31 kb from SYNPO2) in the whole sample and rs6844137 (within the intronic region of SYNPO2) in the European ancestry subsample were associated with a decreased likelihood of remission. In polygenic risk analyses, participants who had greater improvement after antidepressant treatments showed a higher likelihood of reaching remission. Those who achieved remission and had a higher polygenic risk for Alzheimer’s disease had a significantly decreased likelihood of relapse. Conclusion: Our analyses provide preliminary insights into the genetic architecture of remission and relapse in a well-characterized group of patients with psychotic depression.

[1]  Michael F. Green,et al.  Mapping genomic loci implicates genes and synaptic biology in schizophrenia , 2022, Nature.

[2]  M. Rietschel,et al.  Identifying the Common Genetic Basis of Antidepressant Response , 2021, Biological psychiatry global open science.

[3]  B. Mulsant,et al.  Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response , 2021, Translational Psychiatry.

[4]  Xiaocheng Zhu,et al.  Pharmacogenetic association of bi- and triallelic polymorphisms of SLC6A4 with antidepressant response in major depressive disorder. , 2020, Journal of affective disorders.

[5]  B. Mulsant,et al.  Pharmacogenetic Implications for Antidepressant Pharmacotherapy in Late-Life Depression: A Systematic Review of the Literature for Response, Pharmacokinetics and Adverse Drug Reactions. , 2020, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[6]  B. Mulsant,et al.  Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial. , 2019, JAMA.

[7]  Shing Wan Choi,et al.  PRSice-2: Polygenic Risk Score software for biobank-scale data , 2019, GigaScience.

[8]  T. Rein,et al.  Is There a Role of Autophagy in Depression and Antidepressant Action? , 2019, Front. Psychiatry.

[9]  C. Sudlow,et al.  Genome‐wide meta‐analysis identifies 3 novel loci associated with stroke , 2018, Annals of neurology.

[10]  R. Marioni,et al.  Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions , 2018, Nature Neuroscience.

[11]  D. Rujescu,et al.  The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives , 2018, The international journal of neuropsychopharmacology.

[12]  Warren W. Kretzschmar,et al.  Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression , 2017, Nature Genetics.

[13]  D. Posthuma,et al.  Functional mapping and annotation of genetic associations with FUMA , 2017, Nature Communications.

[14]  Melissa J. Green,et al.  Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder , 2017, bioRxiv.

[15]  C. Behl,et al.  The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease , 2017, Front. Mol. Neurosci..

[16]  Marie-Pierre Dubé,et al.  genipe: an automated genome-wide imputation pipeline with automatic reporting and statistical tools , 2016, Bioinform..

[17]  Shane A. McCarthy,et al.  Reference-based phasing using the Haplotype Reference Consortium panel , 2016, Nature Genetics.

[18]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[19]  Joris M. Mooij,et al.  MAGMA: Generalized Gene-Set Analysis of GWAS Data , 2015, PLoS Comput. Biol..

[20]  J. Nielsen,et al.  Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics. , 2014, Molecular & cellular proteomics : MCP.

[21]  M. Tohen,et al.  Predicting diagnostic change among patients diagnosed with first-episode DSM-IV-TR major depressive disorder with psychotic features. , 2013, The Journal of clinical psychiatry.

[22]  A. Rothschild Challenges in the treatment of major depressive disorder with psychotic features. , 2013, Schizophrenia bulletin.

[23]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[24]  K. Tansey,et al.  Contribution of Common Genetic Variants to Antidepressant Response , 2013, Biological Psychiatry.

[25]  Stephan Ripke,et al.  Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies. , 2013, The American journal of psychiatry.

[26]  B. Mulsant,et al.  Sustaining remission of psychotic depression: rationale, design and methodology of STOP-PD ΙΙ , 2013, BMC Psychiatry.

[27]  L. Fañanás,et al.  TPH1, MAOA, Serotonin Receptor 2A and 2C Genes in Citalopram Response: Possible Effect in Melancholic and Psychotic Depression , 2012, Neuropsychobiology.

[28]  C. Correll,et al.  Are antipsychotics or antidepressants needed for psychotic depression? A systematic review and meta-analysis of trials comparing antidepressant or antipsychotic monotherapy with combination treatment. , 2012, The Journal of clinical psychiatry.

[29]  Andrew P Morris,et al.  Basic statistical analysis in genetic case-control studies , 2011, Nature Protocols.

[30]  Anthony F Jorm The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): a review , 2004, International Psychogeriatrics.

[31]  A. Morris,et al.  Data quality control in genetic case-control association studies , 2010, Nature Protocols.

[32]  W A Nolen,et al.  Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine , 2010, Acta psychiatrica Scandinavica.

[33]  F. Pontén,et al.  The Human Protein Atlas—a tool for pathology , 2008, The Journal of pathology.

[34]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[35]  J. Berg,et al.  Myo10 in brain: developmental regulation, identification of a headless isoform and dynamics in neurons , 2006, Journal of Cell Science.

[36]  C. Mazure,et al.  Psychotic depression and mortality. , 2003, The American journal of psychiatry.

[37]  A. Schatzberg,et al.  Prevalence of depressive episodes with psychotic features in the general population. , 2002, The American journal of psychiatry.

[38]  C. Cusin,et al.  Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-httlpr in delusional and nondelusional depression , 2001, Biological Psychiatry.

[39]  E. Smeraldi,et al.  Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine , 1998, Molecular Psychiatry.

[40]  N J Cox,et al.  Evidence of linkage between the serotonin transporter and autistic disorder , 1997, Molecular Psychiatry.

[41]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[42]  M. Hamilton A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[43]  Gerome Breen,et al.  Psychiatric Genomics: An Update and an Agenda , 2017, bioRxiv.

[44]  Mathijs,et al.  3 Population-specific genotype imputations using minimac or IMPUTE 2 , 2018 .

[45]  J. Ballenger A Double-blind Randomized Controlled Trial of Olanzapine Plus Sertraline vs Olanzapine Plus Placebo for Psychotic Depression: The Study of Pharmacotherapy of Psychotic Depression (STOP-PD) , 2011 .

[46]  K. Stage,et al.  [Treatment of psychotic depression]. , 2008, Ugeskrift for laeger.