1 2572 126 EPIGENETICS OF DEPRESSION. MAJOR DEPRESSIVE DISORDER (MDD) IS A LEADING CAUSE OF DISABILITY WORLDWIDE AND IS ASSOCIATED WITH POOR PSYCHOLOGICAL, MEDICAL, AND SOCIOECONOMIC OUTCOMES. ALTHOUGH MUCH HAS BEEN LEARNED ABOUT THE ETIOLOGY AND TREATMENT OPTIONS OF MDD OVER THE PAST DECADE, THERE REMAIN UNANSWERED QUESTIONS THAT POSE CHALLENGES TO IMPROVING ACUTE AND CHRONIC OUTCOMES FOR THOSE WITH MDD. MDD IS A CLINICALLY HETEROGENEOUS DISORDER. GENETIC STUDIES TO DATE HAVE INDICATED A NUMBER OF GENES, INCLUDING TRANSPORTERS, NEUROTRANSMITTERS, NEUROTROPHINS, AND THEIR ASSOCIATED SIGNALING NETWORKS THAT MAY PREDISPOSE INDIVIDUALS TO MDD AND MAY ALSO PREDICT TREATMENT OUTCOMES. HOWEVER, TWIN STUDIES INDICATE THAT GENES ACCOUNT FOR ONLY A SMALL DEGREE OF THE VARIATION IN MDD. THUS, OTHER MECHANISMS, THROUGH EPIGENETIC MARKS, MAY ACT TO FORM A MOLECULAR MEMORY OF PREVIOUS GENE-TO-ENVIRONMENT INTERACTIONS AND TO ESTABLISH VULNERABILITIES (OR, CONVERSELY, RESISTANCE) TO MDD. CURRENT EVIDENCE SUPPORTS A ROLE FOR PRE-, PERI-, AND EARLY POSTNATAL ADVERSITIES AND STRESSFUL LIFE EVENTS INTO ADULTHOOD AFFECTING EPIGENETIC PATTERNS, PROVIDING A MECHANISTIC FOUNDATION TO DEVELOP EPIGENETIC MARKS AS BIOMARKERS FOR MDD. THIS REVIEW PRESENTS THE EVIDENCE SUPPORTING A ROLE FOR EPIGENETIC EFFECTS IN MDD AND IN TREATMENT RESPONSE. WE ALSO DISCUSS THE CONTROVERSY BEHIND MODULATING EPIGENETIC MECHANISMS IN LONG-TERM ANTIDEPRESSANT PHARMACOTHERAPY. 2014 2 2231 32 EPIGENETIC MODIFICATIONS OF MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC DISEASE WHOSE NEUROLOGICAL BASIS AND PATHOPHYSIOLOGY REMAIN POORLY UNDERSTOOD. INITIALLY, IT WAS PROPOSED THAT GENETIC VARIATIONS WERE RESPONSIBLE FOR THE DEVELOPMENT OF THIS DISEASE. NEVERTHELESS, SEVERAL STUDIES WITHIN THE LAST DECADE HAVE PROVIDED EVIDENCE SUGGESTING THAT ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE IN MDD PATHOPHYSIOLOGY. ALTERATIONS IN EPIGENETICS MECHANISM, SUCH AS DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA EXPRESSION COULD FAVOR MDD ADVANCE IN RESPONSE TO STRESSFUL EXPERIENCES AND ENVIRONMENTAL FACTORS. THE AIM OF THIS REVIEW IS TO DESCRIBE GENETIC ALTERATIONS, AND PARTICULARLY ALTERED EPIGENETIC MECHANISMS, THAT COULD BE DETERMINANTS FOR MDD PROGRESS, AND HOW THESE ALTERATIONS MAY ARISE AS USEFUL SCREENING, DIAGNOSIS AND TREATMENT MONITORING BIOMARKERS OF DEPRESSIVE DISORDERS. 2016 3 2288 40 EPIGENETIC REGULATION IN MAJOR DEPRESSION AND OTHER STRESS-RELATED DISORDERS: MOLECULAR MECHANISMS, CLINICAL RELEVANCE AND THERAPEUTIC POTENTIAL. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC, GENERALLY EPISODIC AND DEBILITATING DISEASE THAT AFFECTS AN ESTIMATED 300 MILLION PEOPLE WORLDWIDE, BUT ITS PATHOGENESIS IS POORLY UNDERSTOOD. THE HERITABILITY ESTIMATE OF MDD IS 30-40%, SUGGESTING THAT GENETICS ALONE DO NOT ACCOUNT FOR MOST OF THE RISK OF MAJOR DEPRESSION. ANOTHER FACTOR KNOWN TO ASSOCIATE WITH MDD INVOLVES ENVIRONMENTAL STRESSORS SUCH AS CHILDHOOD ADVERSITY AND RECENT LIFE STRESS. RECENT STUDIES HAVE EMERGED TO SHOW THAT THE BIOLOGICAL IMPACT OF ENVIRONMENTAL FACTORS IN MDD AND OTHER STRESS-RELATED DISORDERS IS MEDIATED BY A VARIETY OF EPIGENETIC MODIFICATIONS. THESE EPIGENETIC MODIFICATION ALTERATIONS CONTRIBUTE TO ABNORMAL NEUROENDOCRINE RESPONSES, NEUROPLASTICITY IMPAIRMENT, NEUROTRANSMISSION AND NEUROGLIA DYSFUNCTION, WHICH ARE INVOLVED IN THE PATHOPHYSIOLOGY OF MDD. FURTHERMORE, EPIGENETIC MARKS HAVE BEEN ASSOCIATED WITH THE DIAGNOSIS AND TREATMENT OF MDD. THE EVALUATION OF EPIGENETIC MODIFICATIONS HOLDS PROMISE FOR FURTHER UNDERSTANDING OF THE HETEROGENEOUS ETIOLOGY AND COMPLEX PHENOTYPES OF MDD, AND MAY IDENTIFY NEW THERAPEUTIC TARGETS. HERE, WE REVIEW PRECLINICAL AND CLINICAL EPIGENETIC FINDINGS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNA, RNA MODIFICATION, AND CHROMATIN REMODELING FACTOR IN MDD. IN ADDITION, WE ELABORATE ON THE CONTRIBUTION OF THESE EPIGENETIC MECHANISMS TO THE PATHOLOGICAL TRAIT VARIABILITY IN DEPRESSION AND DISCUSS HOW SUCH MECHANISMS CAN BE EXPLOITED FOR THERAPEUTIC PURPOSES. 2023 4 641 35 BIOMARKERS OF MAJOR DEPRESSIVE DISORDER: KNOWING IS HALF THE BATTLE. MAJOR DEPRESSIVE DISORDER (MDD) IS A HETEROGENEOUS DISEASE WHICH IS WHY THERE ARE CURRENTLY NO SPECIFIC METHODS TO ACCURATELY TEST THE SEVERITY, ENDOPHENOTYPE OR THERAPY RESPONSE. THIS LACK OF PROGRESS IS PARTLY ATTRIBUTED TO THE COM-PLEXITY AND VARIABILITY OF DEPRESSION, IN ASSOCIATION WITH ANALYTICAL VARIABILITY OF CLINICAL LITERATURE AND THE WIDE NUMBER OF THEORETICALLY COMPLEX BIOMARKERS. THE LITERATURE ACCESSIBLE, INDICATES THAT MARKERS INVOLVED IN INFLAMMATORY, NEURO-TROPHIC AND METABOLIC PROCESSES AND COMPONENTS OF NEUROTRANSMITTERS AND NEUROENDOCRINE SYSTEMS ARE RATHER STRONG INDICATORS TO BE CONSIDERED CLINICALLY AND CAN BE MEASURED THROUGH GENETIC AND EPIGENETIC, TRANSCRIPTOMIC AND PROTEOMIC, METABOLOMICS AND NEUROIMAGING ASSESSMENTS. PROMISING BIOLOGIC SYSTEMS/MARKERS FOUND WERE I.E., GROWTH BIOMARKERS, ENDOCRINE MARKERS, OXIDANT STRESS MARKERS, PROTEOMIC AND CHRONIC INFLAMMATORY MARKERS, ARE DISCUSSED IN THIS REVIEW. SEVERAL LINES OF EVIDENCE SUGGEST THAT A PORTION OF MDD IS A DOPAMINE AGONIST-RESPONSIVE SUBTYPE. THIS REVIEW ANALYZES CONCISE REPORTS ON THE PATHOPHYSIOLOGICAL BIOMARKERS OF MDD AND THERAPEUTIC REACTIONS VIA PERIPHERAL DEVELOPMENTAL FACTORS, INFLAMMATIVE CYTOKINES, ENDOCRINE FACTORS AND METABOLIC MARKERS. VARIOUS LITERATURES ALSO SUPPORT THAT ENDOCRINE AND METABOLISM CHANGES ARE ASSOCIATED WITH MDD. ACCUMULATING EVIDENCE SUGGESTS THAT AT LEAST A PORTION OF MDD PATIENTS SHOW CHARACTERISTICS PATHOLOGICAL CHANGES REGARDING DIFFERENT CLINICAL PATHOLOGICAL BIOMARKERS. BY THIS REVIEW WE SUM UP ALL THE DIFFERENT BIOMARKERS PLAYING AN IMPORTANT ROLE IN THE DETECTION OR TREATMENT OF THE DIFFERENT PATIENTS SUFFERING FROM MDD. THE REVIEW ALSO GIVES AN OVERVIEW OF DIFFERENT BIOMARKER'S PLAYING A POTENTIAL ROLE IN MODULATING EFFECT OF MDD. 2021 5 5164 40 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 6 1329 36 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 7 1722 29 DYSREGULATION OF BRAIN DOPAMINE SYSTEMS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD OR DEPRESSION) IS A DEBILITATING NEUROPSYCHIATRIC SYNDROME WITH GENETIC, EPIGENETIC, AND ENVIRONMENTAL CONTRIBUTIONS. DEPRESSION IS ONE OF THE LARGEST CONTRIBUTORS TO CHRONIC DISEASE BURDEN; IT AFFECTS MORE THAN ONE IN SIX INDIVIDUALS IN THE UNITED STATES. A WIDE ARRAY OF CELLULAR AND MOLECULAR MODIFICATIONS DISTRIBUTED ACROSS A VARIETY OF NEURONAL PROCESSES AND CIRCUITS UNDERLIE THE PATHOPHYSIOLOGY OF DEPRESSION-NO ESTABLISHED MECHANISM CAN EXPLAIN ALL ASPECTS OF THE DISEASE. MDD SUFFERS FROM A VAST TREATMENT GAP WORLDWIDE, AND LARGE NUMBERS OF INDIVIDUALS WHO REQUIRE TREATMENT DO NOT RECEIVE ADEQUATE CARE. THIS MINI-REVIEW FOCUSES ON DYSREGULATION OF BRAIN DOPAMINE (DA) SYSTEMS IN THE PATHOPHYSIOLOGY OF MDD AND DESCRIBING NEW CELLULAR TARGETS FOR POTENTIAL MEDICATION DEVELOPMENT FOCUSED ON DA-MODULATED MICRO-CIRCUITS. WE ALSO EXPLORE HOW NEURODEVELOPMENTAL FACTORS MAY MODIFY RISK FOR LATER EMERGENCE OF MDD, POSSIBLY THROUGH DOPAMINERGIC SUBSTRATES IN THE BRAIN. 2021 8 632 37 BIOLOGICAL CORRELATES OF EARLY LIFE STRESSFUL EVENTS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS THE MOST COMMON PSYCHIATRIC DISORDER AND RESPONDS FOR IMPORTANT PSYCHOSOCIAL CONSEQUENCES. STRESSFUL LIFE EVENTS, ESPECIALLY EARLY LIFE STRESS (ELS), CONTRIBUTE TO AN INCREASED PROBABILITY TO DEVELOP MDD, LEADING IN PARTICULAR TO SEVERE AND CHRONIC MANIFESTATION AND UNFAVORABLE TREATMENT OUTCOME. THE ASSOCIATION BETWEEN ELS AND MDD SEEMS TO HAVE BIOLOGICAL BASES, CONSISTING IN DYSREGULATIONS OCCURRING AT DIFFERENT LEVELS. THE AIM OF THIS NARRATIVE REVIEW IS TO PROPOSE AN OVERVIEW OF THE LITERATURE RANGING FROM GENETIC, EPIGENETIC, EXPRESSION AND PROTEIN TO NEUROIMAGING CORRELATES UNDERLYING THIS RELATIONSHIP. A SEARCH ON PUBMED OF STUDIES ASSESSING BIOLOGICAL CORRELATES OF ELS IN MDD DEVELOPMENT, FOCUSING ON HUMAN STUDIES CONDUCTED IN BOTH PERIPHERAL AND BRAIN TISSUES, WAS PERFORMED. EVIDENCE INDICATED THAT THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND THE SEROTONERGIC, DOPAMINERGIC, NEUROTROPHIN AND OXYTOCIN SYSTEMS MIGHT PLAY A ROLE IN THE MEDIATION BETWEEN ELS AND MDD. THE MOST CONSISTENT RESULTS WERE FOUND FOR GENETIC AND EPIGENETIC STUDIES AND INDICATED A JOINT INVOLVEMENT OF THE SYSTEMS MENTIONED. EXPRESSION STUDIES ARE LESS NUMEROUS AND POINT TO AN INVOLVEMENT OF STRESS-RELATED SYSTEMS. CONCERNING PROTEIN STUDIES, THE MAIN MEDIATORS ARE MARKERS RELATED TO THE INFLAMMATORY AND IMMUNE SYSTEMS. NEUROIMAGING STUDIES AIMING AT EVALUATING BRAIN ALTERATIONS CONNECTING ELS AND MDD IN RELATION TO BIOMARKERS INDICATED THE HIPPOCAMPUS, THE AMYGDALA AND THE FRONTAL CORTEX AS IMPORTANT ANATOMICAL MEDIATORS. THESE FINDINGS CAN BUILD THE BASES FOR FUTURE RESEARCH AND CLINICAL INTERVENTIONS; INDEED, THE CLARIFICATION OF BIOLOGICAL MECHANISMS MEDIATING THE RELATIONSHIP BETWEEN ELS AND MDD CAN LEAD TO NEW AND INDIVIDUALIZED PREVENTIVE AND THERAPEUTIC POSSIBILITIES. 2021 9 6414 34 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 10 6260 28 THE MOLECULAR NEUROBIOLOGY OF CHRONIC PAIN-INDUCED DEPRESSION. THE INCREASING NUMBER OF INDIVIDUALS WITH COMORBIDITIES POSES AN URGENT NEED TO IMPROVE THE MANAGEMENT OF PATIENTS WITH MULTIPLE CO-EXISTING DISEASES. AMONG THESE COMORBIDITIES, CHRONIC PAIN AND MOOD DISORDERS, TWO LONG-LASTING DISABLING CONDITIONS THAT SIGNIFICANTLY REDUCE THE QUALITY OF LIFE, COULD BE CITED FIRST. THE RECENT DEVELOPMENT OF ANIMAL MODELS ACCELERATED THE STUDIES FOCUSING ON THE UNDERLYING MECHANISMS OF THE CHRONIC PAIN AND DEPRESSION/ANXIETY COMORBIDITY. THIS REVIEW PROVIDES AN OVERVIEW OF CLINICAL AND PRE-CLINICAL STUDIES PERFORMED OVER THE PAST TWO DECADES ADDRESSING THE MOLECULAR ASPECTS OF THE COMORBID RELATIONSHIP OF CHRONIC PAIN AND DEPRESSION. WE THUS FOCUSED ON THE STUDIES THAT INVESTIGATED THE MOLECULAR CHARACTERISTICS OF THE COMORBID RELATIONSHIP BETWEEN CHRONIC PAIN AND MOOD DISORDERS, ESPECIALLY MAJOR DEPRESSIVE DISORDERS, FROM THE GENETIC AND EPIGENETIC POINT OF VIEW TO KEY NEUROMODULATORS WHICH HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THIS COMORBIDITY. 2019 11 2011 32 EPIGENETIC BASIS OF MENTAL ILLNESS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION AS WELL AS LIKELY ABNORMALITIES IN GLIAL CELLS. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF MOST MENTAL DISORDERS, THE RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS, PARTICULARLY FOR DEPRESSION AND OTHER STRESS-RELATED SYNDROMES, CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. EXPOSURE TO SUCH ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL VERSUS ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND THE ABERRANT EPIGENETIC REGULATION THAT UNDERLIES THIS DYSREGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. HERE, WE PROVIDE A PROGRESS REPORT OF EPIGENETIC STUDIES OF THE THREE MAJOR PSYCHIATRIC SYNDROMES, DEPRESSION, SCHIZOPHRENIA, AND BIPOLAR DISORDER. WE REVIEW THE LITERATURE DERIVED FROM ANIMAL MODELS OF THESE DISORDERS AS WELL AS FROM STUDIES OF POSTMORTEM BRAIN TISSUE FROM HUMAN PATIENTS. WHILE EPIGENETIC STUDIES OF MENTAL ILLNESS REMAIN AT EARLY STAGES, UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY WITHIN SPECIFIC BRAIN REGIONS TO CAUSE LASTING CHANGES IN DISEASE SUSCEPTIBILITY AND PATHOPHYSIOLOGY IS REVEALING NEW INSIGHT INTO THE ETIOLOGY AND TREATMENT OF THESE CONDITIONS. 2016 12 2963 27 GENETIC AND EPIGENETIC MECHANISMS LINKING PAIN AND PSYCHIATRIC DISORDERS. THE NEUROPHYSIOLOGICAL LINK BETWEEN NEUROPATHIC PAIN AND DEPRESSION REMAINS UNKNOWN DESPITE EVIDENT HIGH COMORBIDITY OF THESE TWO DISORDERS. HOWEVER, THERE IS CONVINCING EVIDENCE THAT GENOTYPE PLAYS A ROLE IN BOTH PAIN AND DEPRESSION. USING VARIOUS TYPES OF GENETIC ANALYSIS - POPULATION GENETICS, CYTOGENETICS AND MOLECULAR TECHNOLOGIES - SPECIFIC GENES HAVE BEEN IMPLICATED IN MEDIATING ALMOST ALL ASPECTS OF NOCICEPTION AND MOOD DISORDERS. THE CURRENT REVIEW ATTEMPTS TO IDENTIFY SPECIFIC GENES AND EPIGENETIC MECHANISMS COMMON TO BOTH DISORDERS. IT IS CONCLUDED THAT EXTERNAL AND INTERNAL FACTORS (INFLAMMATION, STRESS, GENDER, ETC.) THAT CONTRIBUTE TO THE PATHOLOGIES MAY DO SO THROUGH EPIGENETIC MECHANISMS THAT MAY AFFECT EXPRESSION OF THESE PARTICULAR GENES. THE POSSIBLE INVOLVEMENT OF EPIGENETIC REGULATION IN PAIN AND PSYCHIATRIC DISORDERS SUGGESTS THAT TREATMENTS TARGETING EPIGENETIC MECHANISMS THAT MEDIATE ADVERSE LIFE EVENTS SHOULD BE CONSIDERED. 2015 13 2526 31 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 14 110 33 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 15 2917 27 GENE-ENVIRONMENT INTERACTIONS IN COMMON MENTAL DISORDERS: AN UPDATE AND STRATEGY FOR A GENOME-WIDE SEARCH. A DECADE OF RESEARCH HAS DEMONSTRATED THE EXPLANATORY POTENTIAL OF INTERPLAY BETWEEN GENETIC VARIANTS AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF COMMON MENTAL DISORDERS. INITIAL FINDINGS HAVE UNDERGONE TESTS OF REPLICABILITY AND SPECIFICITY. SOME GENE-ENVIRONMENT INTERACTIONS HAVE BEEN CONFIRMED, SOME HAVE NOT REPLICATED AND YET OTHER TURNED OUT TO BE MORE SPECIFIC THAN INITIALLY THOUGHT. SPECIFIC AND COMPLEMENTARY ROLES OF GENETIC FACTORS HAVE BEEN DELINEATED: A COMMON FUNCTIONAL LENGTH POLYMORPHISM IN THE SEROTONIN TRANSPORTER GENE (5-HTTLPR) MODERATED THE EFFECT OF CHILDHOOD MALTREATMENT ON CHRONIC DEPRESSION IN ADULTHOOD, BUT DID NOT SUBSTANTIALLY INFLUENCE THE EFFECTS OF ADULT STRESSFUL LIFE EVENTS ON THE ONSET OF NEW DEPRESSIVE EPISODES; IN CONTRAST, A COMMON FUNCTIONAL POLYMORPHISM IN THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF) MODERATED THE EFFECT OF STRESSFUL LIFE EVENTS IN ADULTHOOD IN TRIGGERING NEW DEPRESSIVE EPISODES, BUT DID NOT INFLUENCE THE EFFECTS OF CHILDHOOD MALTREATMENT. MOLECULAR MECHANISMS UNDERLYING GENE-ENVIRONMENT INTERACTIONS ARE BEING UNCOVERED, INCLUDING DNA METHYLATION AND OTHER EPIGENETIC MODIFICATIONS. NEW GENE-ENVIRONMENT INTERACTIONS CONTINUE TO BE REPORTED, STILL LARGELY FROM HYPOTHESIS-DRIVEN RESEARCH. STATISTICAL AND BIOLOGICAL PRIORITIZATION STRATEGIES ARE PROPOSED TO FACILITATE A SYSTEMATIC DISCOVERY OF NOVEL GENE-ENVIRONMENT INTERACTIONS IN GENOME-WIDE ANALYSES. 2014 16 4321 33 MICRORNAS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH A HIGH PREVALENCE IN THE POPULATION. ALTHOUGH OUR UNDERSTANDING OF ITS PATHOPHYSIOLOGICAL MECHANISMS HAS SIGNIFICANTLY INCREASED OVER THE YEARS, AVAILABLE TREATMENTS STILL PRESENT SEVERAL LIMITATIONS AND ARE NOT EFFECTIVE TO ALL MDD PATIENTS. EPIGENETIC MECHANISMS HAVE RECENTLY BEEN SUGGESTED TO PLAY KEY ROLES IN MDD PATHOGENESIS AND TREATMENT, INCLUDING THE EFFECTS OF SMALL NONCODING RNAS KNOWN AS MICRORNAS (MIRNAS). MIRNAS CAN MODULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY BY INTERFERING WITH THE STABILITY AND TRANSLATION OF MESSENGER RNA MOLECULES AND ARE ALSO KNOWN TO CROSS-TALK WITH OTHER EPIGENETIC MECHANISMS. IN THIS REVIEW, WE WILL SUMMARIZE AND DISCUSS RECENT FINDINGS OF ALTERATIONS IN MIRNAS IN TISSUES OF PATIENTS WITH MDD AND EVIDENCE OF TREATMENT-INDUCED EFFECTS IN THESE MOLECULES. 2019 17 4914 29 PAIN VULNERABILITY: A NEUROBIOLOGICAL PERSPECTIVE. THERE ARE MANY KNOWN RISK FACTORS FOR CHRONIC PAIN CONDITIONS, YET THE BIOLOGICAL UNDERPINNINGS THAT LINK THESE FACTORS TO ABNORMAL PROCESSING OF PAINFUL SIGNALS ARE ONLY JUST BEGINNING TO BE EXPLORED. THIS REVIEW WILL DISCUSS THE POTENTIAL MECHANISMS THAT HAVE BEEN PROPOSED TO UNDERLIE VULNERABILITY AND RESILIENCE TOWARD DEVELOPING CHRONIC PAIN. PARTICULAR FOCUS WILL BE GIVEN TO GENETIC AND EPIGENETIC PROCESSES, PRIMING EFFECTS ON A CELLULAR LEVEL, AND ALTERATIONS IN BRAIN NETWORKS CONCERNED WITH REWARD, MOTIVATION/LEARNING AND DESCENDING MODULATORY CONTROL. ALTHOUGH RESEARCH IN THIS AREA IS STILL IN ITS INFANCY, A BETTER UNDERSTANDING OF HOW PAIN VULNERABILITY EMERGES HAS THE POTENTIAL TO HELP IDENTIFY INDIVIDUALS AT RISK AND MAY OPEN UP NEW THERAPEUTIC AVENUES. 2014 18 6676 34 USING EPIGENETIC TOOLS TO INVESTIGATE ANTIDEPRESSANT RESPONSE. MAJOR DEPRESSIVE DISORDER IS A CHRONIC AND DEBILITATING ILLNESS. IT IS MOST COMMONLY TREATED WITH ANTIDEPRESSANT DRUGS, HOWEVER, AS THE MAJORITY OF PATIENTS DO NOT RESPOND ON THEIR FIRST TRIAL OR FOLLOWING SEVERAL ADEQUATE TRIALS, THERE IS GREAT INTEREST IN IDENTIFYING BIOLOGICAL FACTORS THAT MAY HELP SELECT THE MOST APPROPRIATE TREATMENT FOR EACH PATIENT AND IN UNDERSTANDING BIOLOGICAL PROCESSES THAT MEDIATE TREATMENT RESPONSE. EPIGENETIC FACTORS, SUCH AS NON-CODING RNAS (NCRNAS), HOLD POTENTIAL AS BIOMARKERS OF ANTIDEPRESSANT RESPONSE. IN THIS CHAPTER, WE REVIEW KEY METHODOLOGICAL CONSIDERATIONS WHEN INVESTIGATING NCRNA BIOMARKERS, INCLUDING BIOLOGICAL SAMPLES AND TECHNOLOGIES WHICH HAVE BEEN USED IN THESE STUDIES. SECONDLY, WE SUMMARIZE FINDINGS FROM STUDIES INVESTIGATING NCRNAS IN ANTIDEPRESSANT TREATMENT RESPONSE. FINALLY, WE DISCUSS SOME OF THE FUTURE DIRECTIONS WHICH WILL BE NECESSARY FOR THE DEVELOPMENT OF CLINICALLY RELEVANT EPIGENETIC TOOLS. 2018 19 4591 32 NARRATIVE REVIEW OF THE COMPLEX INTERACTION BETWEEN PAIN AND TRAUMA IN CHILDREN: A FOCUS ON BIOLOGICAL MEMORY, PRECLINICAL DATA, AND EPIGENETIC PROCESSES. THE INCIDENCE AND COLLECTIVE IMPACT OF EARLY ADVERSE EXPERIENCES, TRAUMA, AND PAIN CONTINUE TO INCREASE. THIS UNDERSCORES THE URGENT NEED FOR TRANSLATIONAL EFFORTS BETWEEN CLINICAL AND PRECLINICAL RESEARCH TO BETTER UNDERSTAND THE UNDERLYING MECHANISMS AND DEVELOP EFFECTIVE THERAPEUTIC APPROACHES. AS OUR UNDERSTANDING OF THESE ISSUES IMPROVES FROM STUDIES IN CHILDREN AND ADOLESCENTS, WE CAN CREATE MORE PRECISE PRECLINICAL MODELS AND ULTIMATELY TRANSLATE OUR FINDINGS BACK TO CLINICAL PRACTICE. A MULTIDISCIPLINARY APPROACH IS ESSENTIAL FOR ADDRESSING THE COMPLEX AND WIDE-RANGING EFFECTS OF THESE EXPERIENCES ON INDIVIDUALS AND SOCIETY. THIS NARRATIVE REVIEW AIMS TO (1) DEFINE PAIN AND TRAUMA EXPERIENCES IN CHILDHOOD AND ADOLESCENTS, (2) DISCUSS THE RELATIONSHIP BETWEEN PAIN AND TRAUMA, (3) CONSIDER THE ROLE OF BIOLOGICAL MEMORY, (4) DECIPHER THE RELATIONSHIP BETWEEN PAIN AND TRAUMA USING PRECLINICAL DATA, AND (5) EXAMINE THE ROLE OF THE ENVIRONMENT BY INTRODUCING THE IMPORTANCE OF EPIGENETIC PROCESSES. THE ULTIMATE SCOPE IS TO BETTER UNDERSTAND THE WIDE-RANGING EFFECTS OF TRAUMA, ABUSE, AND CHRONIC PAIN ON CHILDREN AND ADOLESCENTS, HOW THEY OCCUR, AND HOW TO PREVENT OR MITIGATE THEIR EFFECTS AND DEVELOP EFFECTIVE TREATMENT STRATEGIES THAT ADDRESS BOTH THE UNDERLYING CAUSES AND THE ASSOCIATED PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS. 2023 20 38 26 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003