Genes, environment, and individual differences in responding to treatment for depression.
ABSTRACT A principal weakness of evidence-based psychiatry is that it does not account for the individual variability in therapeutic response among individuals with the same diagnosis. The aim of personalized psychiatry is to remediate this shortcoming and to use predictors to select treatment that is most likely to be beneficial for an individual. This article reviews the evidence that genetic variation, environmental exposures, and gene-environment interactions shape mental illness and influence treatment outcomes, with a primary focus on depression. Several genetic polymorphisms have been identified that influence the outcome of specific treatments, but the strength and generalizability of such influences are not sufficient to justify personalized prescribing. Environmental exposures in early life, such as childhood maltreatment, exert long-lasting influences that are moderated by inherited genetic variation and mediated through stable epigenetic mechanisms such as tissue- and gene-specific DNA methylation. Pharmacological and psychological treatments act on and against the background of genetic disposition, with epigenetic annotation resulting from previous experiences. Research in animal models suggests the possibility that epigenetic interventions may modify the impact of environmental stressors on mental health. Gaps in evidence are identified that need to be bridged before knowledge about cause can inform cure in personalized psychiatry.
SourceAvailable from: Andreas Meyer-Lindenberg[Show abstract] [Hide abstract]
ABSTRACT: Modern neuropsychopharmacology commenced in the 1950s with the serendipitous discovery of first-generation antipsychotics and antidepressants which were therapeutically effective yet had marked adverse effects. Today, a broader palette of safer and better-tolerated agents is available for helping people that suffer from schizophrenia, depression and other psychiatric disorders, while complementary approaches like psychotherapy also have important roles to play in their treatment, both alone and in association with medication. Nonetheless, despite considerable efforts, current management is still only partially effective, and highly-prevalent psychiatric disorders of the brain continue to represent a huge personal and socio-economic burden. The lack of success in discovering more effective pharmacotherapy has contributed, together with many other factors, to a relative disengagement by pharmaceutical firms from neuropsychiatry. Nonetheless, interest remains high, and partnerships are proliferating with academic centres which are increasingly integrating drug discovery and translational research into their traditional activities. This is, then, a time of transition and an opportune moment to thoroughly survey the field. Accordingly, the present paper, first, chronicles the discovery and development of psychotropic agents, focusing in particular on their mechanisms of action and therapeutic utility, and how problems faced were eventually overcome. Second, it discusses the lessons learned from past successes and failures, and how they are being applied to promote future progress. Third, it comprehensively surveys emerging strategies that are (1), improving our understanding of the diagnosis and classification of psychiatric disorders; (2), deepening knowledge of their underlying risk factors and pathophysiological substrates; (3), refining cellular and animal models for discovery and validation of novel therapeutic agents; (4), improving the design and outcome of clinical trials; (5), moving towards reliable biomarkers of patient subpopulations and medication efficacy and (6), promoting collaborative approaches to innovation by uniting key partners from the regulators, industry and academia to patients. Notwithstanding the challenges ahead, the many changes and ideas articulated herein provide new hope and something of a framework for progress towards the improved prevention and relief of psychiatric and other CNS disorders, an urgent mission for our Century. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.European Neuropsychopharmacology 02/2015; DOI:10.1016/j.euroneuro.2015.01.016 · 5.40 Impact Factor
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ABSTRACT: Childhood maltreatment (CM) history has been associated with poor treatment response in major depressive disorder (MDD), but the mechanisms underlying this relationship remain opaque. Dysfunction in the neural circuits for executive cognition is a putative neurobiological consequence of CM that may contribute importantly to adverse clinical outcomes. We used behavioral and neuroimaging measures of executive functioning to assess their contribution to the relationship between CM and antidepressant response in MDD patients. Ninety eight medication-free MDD outpatients participating in the International Study to Predict Optimized Treatment in Depression were assessed at baseline on behavioral neurocognitive measures and functional magnetic resonance imaging during tasks probing working memory (continuous performance task, CPT) and inhibition (Go/No-go). Seventy seven patients completed 8 weeks of antidepressant treatment. Baseline behavioral and neuroimaging measures were assessed in relation to CM (history of childhood physical, sexual, and/or emotional abuse) and posttreatment depression outcomes. Patients with maltreatment exhibited decreased modulation of right dorsolateral prefrontal cortex (DLPFC) activity during working memory updating on the CPT, and a corresponding impairment in CPT behavioral performance outside the scanner. No between-group differences were found for imaging or behavior on the Go/No-go test of inhibition. Greater DLPFC activity during CPT significantly predicted posttreatment symptom improvement in patients without maltreatment, whereas the relationship between DLPFC activity and symptom change was nonsignificant, and in the opposite direction, in patients with maltreatment. The effect of CM on prefrontal circuitry involved in executive function is a potential predictor of antidepressant outcomes. © 2015 Wiley Periodicals, Inc.Depression and Anxiety 04/2015; DOI:10.1002/da.22368 · 4.29 Impact Factor
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ABSTRACT: Depression is prevalent in patients with physical disorders, particularly in those with severe disorders such as cancer, stroke, and acute coronary syndrome. Depression has an adverse impact on the courses of these diseases that includes poor quality of life, more functional impairments, and a higher mortality rate. Patients with physical disorders are at higher risk of depression. This is particularly true for patients with genetic and epigenetic predictors, environmental vulnerabilities such as past depression, higher disability, and stressful life events. Such patients should be monitored closely. To appropriately manage depression in these patients, comprehensive and integrative care that includes antidepressant treatment (with considerations for adverse effects and drug interactions), treatment of the physical disorder, and collaborative care that consists of disease education, cognitive reframing, and modification of coping style should be provided. The objective of the present review was to present and summarize the prevalence, risk factors, clinical correlates, current pathophysiological aspects including genetics, and treatments for depression comorbid with physical disorders. In particular, we tried to focus on severe physical disorders with high mortality rates, such as cancer, stroke, and acute coronary syndrome, which are highly comorbid with depression. This review will enhance our current understanding of the association between depression and serious medical conditions, which will allow clinicians to develop more advanced and personalized treatment options for these patients in routine clinical practice.04/2015; 51(1):8-18. DOI:10.4068/cmj.2015.51.1.8