Convergent neurobiological predictors of mood and anxiety symptoms and treatment response

ABSTRACT

Introduction: Mood and anxiety disorders are leading contributors to the global burden of diseases. Comorbid mood and anxiety disorders have a lifetime prevalence of ~20% globally and increases the risk for suicide, a leading cause of death.

Areas covered: In this review, authors highlight recent advances in the understanding of multilevel-neurobiological mechanisms for normal/pathological human affective-functioning. The authors then address the complex interplay between environmental-adversity and molecular-genetic mediators of brain correlates of affective-symptoms. The molecular focus is strategically limited to GTF2i, BDNF, and FKBP5 genes that are, respectively, involved in transcriptional-, neurodevelopmental- and neuroendocrine-pathway mediation of affective-functions. The importance of these genes is illustrated with studies of copy-number-variants, genome-wide association (GWAS), and candidate gene-sequence variant associations with disease etiology. Authors concluded by highlighting the predictive values of integrative neurobiological processing of gene–environment interactions for affective disorder symptom management.

Expert opinion: Given the transcriptional, neurodevelopmental and neuroimmune relevance of GTF2i, BDNF, and FKBP5 genes, respectively, authors reviewed the putative roles of these genes in neurobiological mediation of adaptive affective-responses. Authors discussed the importance of studying gene-dosage effects in understanding affective disorder risk biology, and how such targeted neurogenetic studies could guide precision identification of novel pharmacotherapeutic targets and aid in prediction of treatment response.

KEYWORDS:

• Affect
• depression
• anxiety
• brain
• structure
• function
• genetics
• environment
• treatment
• prediction

Acknowledgements

Authors would like to thank Christine Thomas for providing picture contents for figures 1 & 2, and Wade Weber for edits of an earlier version of the manuscript.

Article highlights

• Several molecular-genetic pathways in interaction with environmental adversity, contribute to prefrontal brain changes underlying affective disorder symptoms.

• These reported structural prefrontal brain abnormalities in affective disorders introduced here as ‘mental scars’ co-occurs with functional and connectivity alterations.

• The directionality of these clinically relevant convergent brain changes, and their symptom-specific characteristics are currently not well understood and requires further integrative studies.

• An integration of genomic, epigenetic, and brain structural/functional (imaging) measures are likely to yield predictive values for individual treatment responses in patients with affective disorders.

Declaration of interest

CB Nemeroff has consulted for Xhale, Takeda, Taisho Pharmaceutical Inc., Bracket (Clintara), Fortress Biotech, Sunovion Pharmaceuticals Inc., Sumitomo Dainippon Pharma, Janssen Research & Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., TC MSO, Inc., Intra-Cellular Therapies, Inc. over the past three years. He is also a stockholder in Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Antares, BI Gen Holdings, Inc., Corcept Therapeutics Pharmaceuticals Company, TC MSO, Inc., Trends in Pharma Development, LLC. He has also served on advisory boards for: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Bracket (Clintara), Laureate Institute for Brain Research (LIBR), Inc. He also sits on the board of directors for: AFSP, Gratitude America and ADAA. He discloses income sources or equity of $10,000 or more from American Psychiatric Publishing, Xhale, Bracket (Clintara), CME Outfitters, Takeda, Intra-Cellular Therapies, Inc., Magstim and EMA Wellness. Finally, he also holds patents for: Method and devices for transdermal delivery of lithium (US 6,375,990B1); Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2); Compounds, Compositions, Methods of Synthesis, and Methods of Treatment (CRF Receptor Binding Ligand) (US 8,551, 996 B2). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

M Jabbi is supported by the University of Texas Dell Medical School; CB Nemeroff is supported by the University of Texas Dell Medical School; National Institutes of Health (NIH) and the Stanley Medical Research Institute