1 4525 95 MULTIFACTORIAL CAUSES OF PARANOID SCHIZOPHRENIA WITH AUDITORY-VISUAL HALLUCINATIONS IN A 31-YEAR-OLD MALE WITH HISTORY OF TRAUMATIC BRAIN INJURY AND SUBSTANCE ABUSE. SCHIZOPHRENIA IS A CHRONIC PSYCHIATRIC DISORDER THAT CLASSICALLY PRESENTS WITH DISTORTIONS OF THOUGHT, BEHAVIOR, AND PERCEPTIONS THAT ARE OFTEN MISDIAGNOSED. ONE DIFFICULTY IN DIAGNOSING SCHIZOPHRENIA IS DUE TO ITS PHENOTYPICALLY HETEROGENEOUS CONDITION THAT CAN BE PRECIPITATED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE PREVALENCE OF SCHIZOPHRENIA IS ROUGHLY 1%, BUT IT IS OFTEN MISDIAGNOSED. POSSIBLE DIFFERENTIAL DIAGNOSES INCLUDE DEPRESSION OR BIPOLAR DISORDER WITH PSYCHOSIS, PSYCHOSIS DUE TO A MEDICAL CONDITION, SCHIZOTYPAL AND SCHIZOID PERSONALITY DISORDERS, AND NEUROCOGNITIVE DISORDERS. IN THIS CASE REPORT, A 31-YEAR-OLD MALE PRESENTS WITH THOUGHTS OF SUICIDE FOLLOWING A RECENT EXACERBATION OF HIS HALLUCINATIONS. ON PRESENTATION, THE PATIENT PRESENTED WITH A HISTORICAL DIAGNOSIS OF "PARANOID SCHIZOPHRENIA" AS WELL AS A HISTORY OF TRAUMATIC BRAIN INJURY (TBI), POLY-SUBSTANCE USE DISORDER, AND A FAMILY HISTORY OF SCHIZOPHRENIA. THIS CASE SERVES TO HIGHLIGHT THE DIFFICULTIES OF MAKING AN ACCURATE DIAGNOSIS AND PROVIDING EVIDENCED-BASED TREATMENT. 2022 2 1810 20 EFFECTS OF ANTIPSYCHOTICS ON THE BDNF IN SCHIZOPHRENIA. BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IS INVOLVED IN THE DEVELOPMENT OF THE BRAIN, AND LIKELY INFLUENCES THE NEUROPLASTICITY IN SCHIZOPHRENIA. BDNF IS ALSO BELIEVED TO INTERACT WITH OTHER NEUROTRANSMITTER SYSTEMS IMPLICATED IN SCHIZOPHRENIA, SUCH AS DOPAMINE, GLUTAMATE, SEROTONIN AND GABA. THEREFORE, BDNF IS A CANDIDATE GENE FOR SCHIZOPHRENIA. IN PAST DECADES, THE BLOOD (SERUM OR PLASMA) BDNF PROTEIN LEVELS AND BDNF GENE ALLELES AND GENOTYPES TO THE CLINICAL FEATURES OF SCHIZOPHRENIA, SUCH AS AGE OF ONSET, CLINICAL SUBTYPES, SYMPTOM SEVERITY, AND DRUG RESPONSE, HAVE BEEN EVALUATED AMONG DIFFERENT POPULATIONS. HOWEVER, THE RESULTS ARE STILL INCONSISTENT. FURTHER, DIFFERENT DRUGS HAVE BEEN REPORTED TO HAVE DIFFERENT EFFECTS ON BDNF PROTEIN LEVELS. A CROSS-SECTIONAL SURVEY REVEALED THAT SERUM BDNF LEVELS IN CHRONIC SCHIZOPHRENIC PATIENTS TREATED WITH CLOZAPINE EXCEEDED THOSE OF PATIENTS TREATED WITH RISPERIDONE OR WITH TYPICAL ANTIPSYCHOTICS. IN RECENT TIMES, BDNF EPIGENETIC STUDIES HAVE ALSO BEEN CONDUCTED IN CLINICAL STUDIES OF SCHIZOPHRENIA TO ADDRESS THE QUESTION OF WHY PATIENTS WITH THE SAME GENE GENOTYPE AND ALLELES HAVE DIFFERENT CLINICAL PRESENTATIONS. IN ADDITION, THE EFFECTS OF DIFFERENT ANTIPSYCHOTIC DRUGS ON GENE METHYLATION AND PROTEIN ACETYLATION HAVE ALSO BEEN REPORTED. IN CONCLUSION, MORE DATA ARE NEEDED REGARDING BDNF IN THE BRAIN AND IN PERIPHERAL BLOOD, INCLUDING PROTEIN LEVELS, SINGLE NUCLEOTIDE POLYMORPHISMS, EPIGENETIC REGULATION, AND CLINICAL DATA IN ORDER TO UNDERSTAND THE ROLE OF BDNF IN SCHIZOPHRENIA. 2013 3 4390 28 MODELING THE MOLECULAR EPIGENETIC PROFILE OF PSYCHOSIS IN PRENATALLY STRESSED MICE. BASED ON POSTMORTEM BRAIN STUDIES, OUR OVERARCHING EPIGENETIC HYPOTHESIS IS THAT CHRONIC SCHIZOPHRENIA (SZ) IS A PSYCHOPATHOLOGICAL CONDITION INVOLVING DYSREGULATION OF THE DYNAMIC EQUILIBRIUM AMONG DNA METHYLATION/DEMETHYLATION NETWORK COMPONENTS AND THE EXPRESSION OF SZ TARGET GENES, INCLUDING GABAERGIC AND GLUTAMATERGIC GENES. SZ HAS A NATURAL COURSE, STARTING WITH A PRODROMAL PHASE, A FIRST EPISODE THAT OCCURS IN ADOLESCENTS OR IN YOUNG ADULTS, AND LATER DETERIORATION OVER THE ADULT YEARS. HENCE, THE EPIGENETIC STATUS AT EACH NEURODEVELOPMENTAL STAGE OF THE DISEASE CANNOT BE STUDIED JUST IN POSTMORTEM BRAIN OF CHRONIC SZ PATIENTS, BUT REQUIRES THE USE OF NEURODEVELOPMENTAL ANIMAL MODELS. WE HAVE DIRECTED THE FOCUS OF OUR RESEARCH TOWARD STUDYING THE EPIGENETIC SIGNATURE OF THE SZ BRAIN IN THE OFFSPRING OF DAMS STRESSED DURING PREGNANCY (PRS MICE). ADULT PRS MICE HAVE BEHAVIORAL DEFICITS REMINISCENT OF BEHAVIORS OBSERVED IN PSYCHOTIC PATIENTS. THE ADULT PRS BRAIN, LIKE THAT OF POSTMORTEM CHRONIC SZ PATIENTS, IS CHARACTERIZED BY A SIGNIFICANT INCREASE IN DNA METHYLTRANSFERASE 1, TET METHYLCYTOSINE DIOXYGENASE 1 (TET1), 5-METHYLCYTOSINE, AND 5-HYDROXYMETHYLCYTOSINE AT SZ CANDIDATE GENE PROMOTERS AND A REDUCTION IN THE EXPRESSION OF GLUTAMATERGIC AND GABAERGIC GENES. IN PRS MICE, MEASUREMENTS OF EPIGENETIC BIOMARKERS FOR SZ CAN BE ASSESSED AT DIFFERENT STAGES OF DEVELOPMENT WITH THE GOAL OF FURTHER ELUCIDATING THE PATHOPHYSIOLOGY OF THIS DISEASE AND PREDICTING TREATMENT RESPONSES AT SPECIFIC STAGES OF THE ILLNESS, WITH PARTICULAR ATTENTION TO EARLY DETECTION AND POSSIBLY EARLY INTERVENTION. 2014 4 1538 24 DNA METHYLATION IN ANIMAL MODELS OF PSYCHOSIS. SCHIZOPHRENIA (SZ) IS A DEBILITATING DISEASE THAT IMPACTS 1% OF THE POPULATION WORLDWIDE. ASSOCIATION STUDIES HAVE SHOWN THAT INHERITED GENETIC MUTATIONS ACCOUNT FOR A PORTION OF DISEASE RISK. HOWEVER, ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF THE DISEASE BY ALTERING CELLULAR EPIGENETIC MARKS AT THE LEVEL OF CHROMATIN. POSTMORTEM BRAIN STUDIES OF SZ SUBJECTS SUGGEST THAT THE DYNAMIC EQUILIBRIUM BETWEEN DNA METHYLATION AND DEMETHYLATION NETWORK COMPONENTS IS DISRUPTED AT THE LEVEL OF INDIVIDUAL SZ TARGET GENES. HEREIN, WE REVIEW THE ROLE OF DNA METHYLATION AND DEMETHYLATION IN THE CONTEXT OF WHAT IS CURRENTLY KNOWN REGARDING SZ. FURTHERMORE, WE DESCRIBE THE DEFICITS THAT ACCOMPANY TWO MOUSE MODELS OF SZ. THE CHRONIC METHIONINE MOUSE MODEL OF SZ IS PREDICATED ON THE ADMINISTRATION OF METHIONINE TO SZ PATIENTS AND CONTROLS IN THE CONTEXT OF CLINICAL STUDIES THAT WERE CARRIED OUT DURING THE 1960S AND 1970S. THE PRENATAL RESTRAINT STRESS MODEL OF SZ IS BASED ON A PROLONGED STRESS PARADIGM ADMINISTERED TO PREGNANT DAMS DURING GESTATION DAYS 7-21. THE ADULT OFFSPRING OF THESE DAMS SHOW VARIOUS BEHAVIORAL AND BIOCHEMICAL DEFICITS IN ADULTHOOD. BOTH MODELS ARE EPIGENETIC IN ORIGIN AND MIMIC THE POSITIVE AND NEGATIVE SYMPTOMS, AS WELL AS THE COGNITIVE ENDOPHENOTYPES COMMONLY OBSERVED IN SZ PATIENTS. WE ALSO DISCUSS THE UTILITY OF TYPICAL AND ATYPICAL ANTIPSYCHOTIC DRUGS IN ALLEVIATING THESE SYMPTOMS IN EACH MODEL. 2018 5 5302 26 PROTEIN-C REACTIVE AS BIOMARKER PREDICTOR OF SCHIZOPHRENIA PHASES OF ILLNESS? A SYSTEMATIC REVIEW. BACKGROUND: SCHIZOPHRENIA IS A COMPLEX ILLNESS IN WHICH GENETIC, ENVIRONMENTAL, AND EPIGENETIC COMPONENTS HAVE BEEN IMPLICATED. HOWEVER, RECENTLY, PSYCHIATRIC DISORDERS APPEAR TO BE RELATED TO A CHRONIC INFLAMMATORY STATE, AT THE LEVEL OF SPECIFIC CEREBRAL AREAS WHICH HAVE BEEN FOUND AS WELL IMPAIRED AND RESPONSIBLE FOR SCHIZOPHRENIA SYMPTOMATOLOGY. HENCE, A ROLE OF INFLAMMATORY MEDIATORS AND CYTOKINES HAS BEEN AS WELL DEFINED. ACCORDINGLY, THE ROLE OF AN ACUTE INFLAMMATORY PHASE PROTEIN, THE C-REACTIVE PROTEIN (CRP) HAS BEEN RECENTLY INVESTIGATED. OBJECTIVE: THE OBJECTIVE OF THE PRESENT STUDY IS TO EVALUATE HOW PCR MAY REPRESENT A BIOMARKER IN SCHIZOPHRENIA, I.E. CORRELATED WITH ILLNESS PHASES AND/OR CLINICAL MANIFESTATION AND/OR PSYCHOPATHOLOGICAL SEVERITY. METHODS: A SYSTEMATIC REVIEW WAS HERE CARRIED OUT BY SEARCHING THE FOLLOWING KEYWORDS ((C-REACTIVE PROTEIN AND ((SCHIZOPHRENIA) OR (PSYCHOTIC DISORDER))) FOR THE TOPICS 'PCR' AND 'SCHIZOPHRENIA', BY USING MESH TERMS. RESULTS: AN IMMUNE DYSFUNCTION AND INFLAMMATION HAVE BEEN DESCRIBED AMONGST SCHIZOPHRENIC PATIENTS. FINDINGS REPORTED ELEVATED CRP LEVELS IN SCHIZOPHRENIA, MAINLY CORRELATED WITH THE SEVERITY OF ILLNESS AND DURING THE RECRUDESCENT PHASE. CRP LEVELS ARE HIGHER WHEN CATATONIC FEATURES, NEGATIVE SYMPTOMATOLOGY AND AGGRESSIVENESS ARE ASSOCIATED. CRP LEVELS APPEARED NOT TO BE RELATED TO SUICIDAL BEHAVIOUR AND IDEATION. CONCLUSION: CRP AND ITS BLOOD LEVELS HAVE BEEN REPORTED HIGHER AMONGST SCHIZOPHRENIC PATIENTS, BY SUGGESTING A ROLE OF INFLAMMATION IN THE PATHOGENESIS OF SCHIZOPHRENIA. FURTHER STUDIES ARE NEEDED TO BETTER UNDERSTAND IF CRP MAY BE CONSIDERED A BIOMARKER IN SCHIZOPHRENIA. 2018 6 252 27 ADVANCEMENTS IN THE UNDERLYING PATHOGENESIS OF SCHIZOPHRENIA: IMPLICATIONS OF DNA METHYLATION IN GLIAL CELLS. SCHIZOPHRENIA (SZ) IS A CHRONIC AND SEVERE MENTAL ILLNESS FOR WHICH CURRENTLY THERE IS NO CURE. AT PRESENT, THE EXACT MOLECULAR MECHANISM INVOLVED IN THE UNDERLYING PATHOGENESIS OF SZ IS UNKNOWN. THE DISEASE IS THOUGHT TO BE CAUSED BY A COMBINATION OF GENETIC, BIOLOGICAL, PSYCHOLOGICAL, AND ENVIRONMENTAL FACTORS. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC REGULATION IS INVOLVED IN SZ PATHOLOGY. SPECIFICALLY, DNA METHYLATION, ONE OF THE EARLIEST FOUND EPIGENETIC MODIFICATIONS, HAS BEEN EXTENSIVELY LINKED TO MODULATION OF NEURONAL FUNCTION, LEADING TO PSYCHIATRIC DISORDERS SUCH AS SZ. HOWEVER, INCREASING EVIDENCE INDICATES THAT GLIAL CELLS, ESPECIALLY DYSFUNCTIONAL OLIGODENDROCYTES UNDERGO DNA METHYLATION CHANGES THAT CONTRIBUTE TO THE PATHOGENESIS OF SZ. THIS REVIEW PRIMARILY FOCUSES ON DNA METHYLATION INVOLVED IN GLIAL DYSFUNCTIONS IN SZ. CLARIFYING THIS MECHANISM MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONAL STRATEGIES FOR THE TREATMENT OF SZ AND OTHER ILLNESSES BY CORRECTING ABNORMAL METHYLATION IN GLIAL CELLS. 2015 7 3534 24 IMMEDIATE-EARLY GENES MODULATION BY ANTIPSYCHOTICS: TRANSLATIONAL IMPLICATIONS FOR A PUTATIVE GATEWAY TO DRUG-INDUCED LONG-TERM BRAIN CHANGES. AN INCREASING AMOUNT OF RESEARCH AIMS AT RECOGNIZING THE MOLECULAR MECHANISMS INVOLVED IN LONG-LASTING BRAIN ARCHITECTURAL CHANGES INDUCED BY ANTIPSYCHOTIC TREATMENTS. ALTHOUGH BOTH STRUCTURAL AND FUNCTIONAL MODIFICATIONS HAVE BEEN IDENTIFIED FOLLOWING ACUTE ANTIPSYCHOTIC ADMINISTRATION IN HUMANS, CURRENTLY THERE IS SCARCE KNOWLEDGE ON THE ENDURING CONSEQUENCES OF THESE ACUTE CHANGES. NEW INSIGHTS IN IMMEDIATE-EARLY GENES (IEGS) MODULATION FOLLOWING ACUTE OR CHRONIC ANTIPSYCHOTIC ADMINISTRATION MAY HELP TO FILL THE GAP BETWEEN PRIMARY MOLECULAR RESPONSE AND PUTATIVE LONG-TERM CHANGES. MOREOVER, A CRITICAL APPRAISAL OF THE SPATIAL AND TEMPORAL PATTERNS OF IEGS EXPRESSION MAY SHED LIGHT ON THE FUNCTIONAL "SIGNATURE" OF ANTIPSYCHOTICS, SUCH AS THE PROPENSITY TO INDUCE MOTOR SIDE EFFECTS, THE POTENTIAL NEUROBIOLOGICAL MECHANISMS UNDERLYING THE DIFFERENCES BETWEEN ANTIPSYCHOTICS BEYOND D2 DOPAMINE RECEPTOR AFFINITY, AS WELL AS THE RELEVANT EFFECTS OF BRAIN REGION-SPECIFICITY IN THEIR MECHANISMS OF ACTION. THE INTEREST FOR BRAIN IEGS MODULATION AFTER ANTIPSYCHOTIC TREATMENTS HAS BEEN REVITALIZED BY BREAKTHROUGH FINDINGS SUCH AS THE ROLE OF EARLY GENES IN SCHIZOPHRENIA PATHOPHYSIOLOGY, THE INVOLVEMENT OF IEGS IN EPIGENETIC MECHANISMS RELEVANT FOR COGNITION, AND IN NEURONAL MAPPING BY MEANS OF IEGS EXPRESSION PROFILING. HERE WE CRITICALLY REVIEW THE EVIDENCE ON THE DIFFERENTIAL MODULATION OF IEGS BY ANTIPSYCHOTICS, HIGHLIGHTING THE ASSOCIATION BETWEEN IEGS EXPRESSION AND NEUROPLASTICITY CHANGES IN BRAIN REGIONS IMPACTED BY ANTIPSYCHOTICS, TRYING TO ELUCIDATE THE MOLECULAR MECHANISMS UNDERPINNING THE EFFECTS OF THIS CLASS OF DRUGS ON PSYCHOTIC, COGNITIVE AND BEHAVIORAL SYMPTOMS. 2017 8 3283 29 HIDDEN ROLE OF GUT MICROBIOME DYSBIOSIS IN SCHIZOPHRENIA: ANTIPSYCHOTICS OR PSYCHOBIOTICS AS THERAPEUTICS? SCHIZOPHRENIA IS A CHRONIC, HETEROGENEOUS NEURODEVELOPMENTAL DISORDER THAT HAS COMPLEX SYMPTOMS AND UNCERTAIN ETIOLOGY. MOUNTING EVIDENCE INDICATES THE INVOLVEMENT OF GENETICS AND EPIGENETIC DISTURBANCES, ALTERATION IN GUT MICROBIOME, IMMUNE SYSTEM ABNORMALITIES, AND ENVIRONMENTAL INFLUENCE IN THE DISEASE, BUT A SINGLE ROOT CAUSE AND MECHANISM INVOLVED HAS YET TO BE CONCLUSIVELY DETERMINED. CONSEQUENTLY, THE IDENTIFICATION OF DIAGNOSTIC MARKERS AND THE DEVELOPMENT OF PSYCHOTIC DRUGS FOR THE TREATMENT OF SCHIZOPHRENIA FACES A HIGH FAILURE RATE. THIS ARTICLE SURVEYS THE ETIOLOGY OF SCHIZOPHRENIA WITH A PARTICULAR FOCUS ON GUT MICROBIOTA REGULATION AND THE MICROBIAL SIGNALING SYSTEM THAT CORRELATES WITH THE BRAIN THROUGH THE VAGUS NERVE, ENTERIC NERVOUS SYSTEM, IMMUNE SYSTEM, AND PRODUCTION OF POSTBIOTICS. GUT MICROBIALLY PRODUCED MOLECULES MAY LAY THE GROUNDWORK FOR FURTHER INVESTIGATIONS INTO THE ROLE OF GUT MICROBIOTA DYSBIOSIS AND THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA. CURRENT TREATMENT OF SCHIZOPHRENIA IS LIMITED TO PSYCHOTHERAPY AND ANTIPSYCHOTIC DRUGS THAT HAVE SIGNIFICANT SIDE EFFECTS. THEREFORE, ALTERNATIVE THERAPEUTIC OPTIONS MERIT EXPLORATION. THE USE OF PSYCHOBIOTICS ALONE OR IN COMBINATION WITH ANTIPSYCHOTICS MAY PROMOTE THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES. IN VIEW OF THE INDIVIDUAL GUT MICROBIOME STRUCTURE AND PERSONALIZED RESPONSE TO ANTIPSYCHOTIC DRUGS, A TAILORED AND TARGETED MANIPULATION OF GUT MICROBIAL DIVERSITY NATURALLY BY NOVEL PREBIOTICS (NON-DIGESTIBLE FIBER) MAY BE A SUCCESSFUL ALTERNATIVE THERAPEUTIC FOR THE TREATMENT OF SCHIZOPHRENIA PATIENTS. 2021 9 579 26 BEHAVIORAL AND MOLECULAR NEUROEPIGENETIC ALTERATIONS IN PRENATALLY STRESSED MICE: RELEVANCE FOR THE STUDY OF CHROMATIN REMODELING PROPERTIES OF ANTIPSYCHOTIC DRUGS. WE HAVE RECENTLY REPORTED THAT MICE BORN FROM DAMS STRESSED DURING PREGNANCY (PRS MICE), IN ADULTHOOD, HAVE BEHAVIORAL DEFICITS REMINISCENT OF BEHAVIORS OBSERVED IN SCHIZOPHRENIA (SZ) AND BIPOLAR (BP) DISORDER PATIENTS. FURTHERMORE, WE HAVE SHOWN THAT THE FRONTAL CORTEX (FC) AND HIPPOCAMPUS OF ADULT PRS MICE, LIKE THAT OF POSTMORTEM CHRONIC SZ PATIENTS, ARE CHARACTERIZED BY INCREASES IN DNA-METHYLTRANSFERASE 1 (DNMT1), TEN-ELEVEN METHYLCYTOSINE DIOXYGENASE 1 (TET1) AND EXHIBIT AN ENRICHMENT OF 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) AT NEOCORTICAL GABAERGIC AND GLUTAMATERGIC GENE PROMOTERS. HERE, WE SHOW THAT THE BEHAVIORAL DEFICITS AND THE INCREASED 5MC AND 5HMC AT GLUTAMIC ACID DECARBOXYLASE 67 (GAD1), REELIN (RELN) AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTERS AND THE REDUCED EXPRESSION OF THE MESSENGER RNAS (MRNAS) AND PROTEINS CORRESPONDING TO THESE GENES IN FC OF ADULT PRS MICE IS REVERSED BY TREATMENT WITH CLOZAPINE (5 MG KG(-1) TWICE A DAY FOR 5 DAYS) BUT NOT BY HALOPERIDOL (1 MG KG(-1) TWICE A DAY FOR 5 DAYS). INTERESTINGLY, CLOZAPINE HAD NO EFFECT ON EITHER THE BEHAVIOR, PROMOTER METHYLATION OR THE EXPRESSION OF THESE MRNAS AND PROTEINS WHEN ADMINISTERED TO OFFSPRING OF NONSTRESSED PREGNANT MICE. CLOZAPINE, BUT NOT HALOPERIDOL, REDUCED THE ELEVATED LEVELS OF DNMT1 AND TET1, AS WELL AS THE ELEVATED LEVELS OF DNMT1 BINDING TO GAD1, RELN AND BDNF PROMOTERS IN PRS MICE SUGGESTING THAT CLOZAPINE, UNLIKE HALOPERIDOL, MAY LIMIT DNA METHYLATION BY INTERFERING WITH DNA METHYLATION DYNAMICS. WE CONCLUDE THAT THE PRS MOUSE MODEL MAY BE USEFUL PRECLINICALLY IN SCREENING FOR THE POTENTIAL EFFICACY OF ANTIPSYCHOTIC DRUGS ACTING ON ALTERED EPIGENETIC MECHANISMS. FURTHERMORE, PRS MICE MAY BE INVALUABLE FOR UNDERSTANDING THE ETIOPATHOGENESIS OF SZ AND BP DISORDER AND FOR PREDICTING TREATMENT RESPONSES AT EARLY STAGES OF THE ILLNESS ALLOWING FOR EARLY DETECTION AND REMEDIAL INTERVENTION. 2016 10 1179 23 CONVERGENCE AND DIVERGENCE IN THE ETIOLOGY OF MYELIN IMPAIRMENT IN PSYCHIATRIC DISORDERS AND DRUG ADDICTION. IMPAIRMENT OF OLIGODENDROGLIA (OL)-DEPENDENT MYELINATION IN THE CENTRAL NERVOUS SYSTEM (CNS) IS A REMARKABLE PARALLEL RECENTLY IDENTIFIED IN MAJOR PSYCHIATRIC DISORDERS AND CHRONIC DRUG ABUSE. NEUROIMAGING AND NEUROPATHOLOGICAL STUDIES REVEALED MYELIN DEFECTS AND MICROARRAY-PROFILING ANALYSIS DEMONSTRATED ABERRANT EXPRESSION OF MYELIN-RELATED GENES IN SCHIZOPHRENIA (SZ), BIPOLAR DISORDER (BD), MAJOR DEPRESSIVE DISORDER (MDD) AND COCAINE ADDICTION. HOWEVER, THE ETIOLOGY UNDERLYING MYELIN IMPAIRMENT IN THESE CLINICALLY DISTINCT SUBJECTS REMAINS ELUSIVE. THIS ARTICLE REVIEWS MYELIN IMPAIRMENT IN LINE WITH DOPAMINERGIC DYSFUNCTION, A PRIME NEUROPATHOPHYSIOLOGICAL TRAIT SHARED IN PSYCHIATRIC DISORDERS AND DRUG ABUSE, AS WELL AS THE GENETIC AND EPIGENETIC ALTERATIONS ASSOCIATED WITH THESE DISEASES. THE CURRENT FINDINGS SUPPORT THE HYPOTHESIS THAT ABERRANT DOPAMINE (DA) ACTION ON OLS IS A COMMON PATHOLOGIC MECHANISM FOR MYELIN IMPAIRMENT IN THE AFOREMENTIONED MENTAL MORBIDITIES, WHEREAS INHERITED GENETIC VARIATIONS THAT SPECIFICALLY AFFECT OL DEVELOPMENT AND MYELINOGENESIS MAY FURTHER INCREASE MYELIN VULNERABILITY IN PSYCHIATRIC DISORDERS. IMPORTANTLY, OL DEFECT IS NOT ONLY A PATHOLOGICAL CONSEQUENCE BUT ALSO A CAUSATIVE FACTOR FOR DOPAMINERGIC DYSFUNCTION. HENCE, MYELIN IMPAIRMENT IS A KEY FACTOR IN THE PATHOGENIC LOOP OF PSYCHIATRIC DISEASES AND DRUG ADDICTION. 2008 11 4758 26 NOVEL TREATMENT STRATEGIES TARGETING MYELIN AND OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA. OLIGODENDROCYTES ARE THE GLIAL CELLS RESPONSIBLE FOR THE FORMATION OF THE MYELIN SHEATH AROUND AXONS. DURING NEURODEVELOPMENT, OLIGODENDROCYTES UNDERGO MATURATION AND DIFFERENTIATION, AND LATER REMYELINATION IN ADULTHOOD. ABNORMALITIES IN THESE PROCESSES HAVE BEEN ASSOCIATED WITH BEHAVIORAL AND COGNITIVE DYSFUNCTIONS AND THE DEVELOPMENT OF VARIOUS MENTAL ILLNESSES LIKE SCHIZOPHRENIA. SEVERAL STUDIES HAVE IMPLICATED OLIGODENDROCYTE DYSFUNCTION AND MYELIN ABNORMALITIES IN THE DISORDER, TOGETHER WITH ALTERED EXPRESSION OF MYELIN-RELATED GENES SUCH AS OLIG2, CNP, AND NRG1. HOWEVER, THE MOLECULAR MECHANISMS SUBJACENT OF THESE ALTERATIONS REMAIN ELUSIVE. SCHIZOPHRENIA IS A SEVERE, CHRONIC PSYCHIATRIC DISORDER AFFECTING MORE THAN 23 MILLION INDIVIDUALS WORLDWIDE AND ITS SYMPTOMS USUALLY APPEAR AT THE BEGINNING OF ADULTHOOD. CURRENTLY, THE MAJOR THERAPEUTIC STRATEGY FOR SCHIZOPHRENIA RELIES ON THE USE OF ANTIPSYCHOTICS. DESPITE THEIR WIDESPREAD USE, THE EFFECTS OF ANTIPSYCHOTICS ON GLIAL CELLS, ESPECIALLY OLIGODENDROCYTES, REMAIN UNCLEAR. THUS, IN THIS REVIEW WE HIGHLIGHT THE CURRENT KNOWLEDGE REGARDING OLIGODENDROCYTE DYSFUNCTION IN SCHIZOPHRENIA, COMPILING DATA FROM (EPI)GENETIC STUDIES AND UP-TO-DATE MODELS TO INVESTIGATE THE ROLE OF OLIGODENDROCYTES IN THE DISORDER. IN ADDITION, WE EXAMINED POTENTIAL TARGETS CURRENTLY INVESTIGATED FOR THE IMPROVEMENT OF SCHIZOPHRENIA SYMPTOMS. RESEARCH IN THIS AREA HAS BEEN INVESTIGATING POTENTIAL BENEFICIAL COMPOUNDS, INCLUDING THE D-AMINO ACIDS D-ASPARTATE AND D-SERINE, THAT ACT AS NMDA RECEPTOR AGONISTS, MODULATING THE GLUTAMATERGIC SIGNALING; THE ANTIOXIDANT N-ACETYLCYSTEINE, A PRECURSOR IN THE SYNTHESIS OF GLUTATHIONE, PROTECTING AGAINST THE REDOX IMBALANCE; AS WELL AS LITHIUM, AN INHIBITOR OF GLYCOGEN SYNTHASE KINASE 3BETA (GSK3BETA) SIGNALING, CONTRIBUTING TO OLIGODENDROCYTE SURVIVAL AND FUNCTIONING. IN CONCLUSION, THERE IS STRONG EVIDENCE LINKING OLIGODENDROCYTE DYSFUNCTION TO THE DEVELOPMENT OF SCHIZOPHRENIA. HENCE, A BETTER UNDERSTANDING OF OLIGODENDROCYTE DIFFERENTIATION, AS WELL AS THE EFFECTS OF ANTIPSYCHOTIC MEDICATION IN THESE CELLS, COULD HAVE POTENTIAL IMPLICATIONS FOR UNDERSTANDING THE DEVELOPMENT OF SCHIZOPHRENIA AND FINDING NEW TARGETS FOR DRUG DEVELOPMENT. 2020 12 4206 28 METABOTROPIC GLUTAMATE 2/3 RECEPTORS AND EPIGENETIC MODIFICATIONS IN PSYCHOTIC DISORDERS: A REVIEW. SCHIZOPHRENIA AND BIPOLAR DISORDER ARE CHRONIC PSYCHIATRIC DISORDERS, BOTH CONSIDERED AS "MAJOR PSYCHOSIS"; THEY ARE THOUGHT TO SHARE SOME PATHOGENETIC FACTORS INVOLVING A DYSFUNCTIONAL GENE X ENVIRONMENT INTERACTION. ALTERATIONS IN THE GLUTAMATERGIC TRANSMISSION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF PSYCHOSIS. OUR GROUP DEVELOPED AN EPIGENETIC MODEL OF SCHIZOPHRENIA ORIGINATED BY PRENATAL RESTRAINT STRESS (PRS) PARADIGM IN MICE. PRS MICE DEVELOPED SOME BEHAVIORAL ALTERATIONS OBSERVED IN SCHIZOPHRENIC PATIENTS AND CLASSIC ANIMAL MODELS OF SCHIZOPHRENIA, I.E. DEFICITS IN SOCIAL INTERACTION, LOCOMOTOR ACTIVITY AND PREPULSE INHIBITION. THEY ALSO SHOWED SPECIFIC CHANGES IN PROMOTER DNA METHYLATION ACTIVITY OF GENES RELATED TO SCHIZOPHRENIA SUCH AS REELIN, BDNF AND GAD67, AND ALTERED EXPRESSION AND FUNCTION OF MGLU2/3 RECEPTORS IN THE FRONTAL CORTEX. INTERESTINGLY, BEHAVIORAL AND MOLECULAR ALTERATIONS WERE REVERSED BY TREATMENT WITH MGLU2/3 AGONISTS. BASED ON THESE FINDINGS, WE SPECULATE THAT PHARMACOLOGICAL MODULATION OF THESE RECEPTORS COULD HAVE A GREAT IMPACT ON EARLY PHASE TREATMENT OF PSYCHOSIS TOGETHER WITH THE POSSIBILITY TO MODULATE SPECIFIC EPIGENETIC KEY PROTEIN INVOLVED IN THE DEVELOPMENT OF PSYCHOSIS. IN THIS REVIEW, WE WILL DISCUSS IN MORE DETAILS THE SPECIFIC FEATURES OF THE PRS MICE AS A SUITABLE EPIGENETIC MODEL FOR MAJOR PSYCHOSIS. WE WILL THEN FOCUS ON KEY PROTEINS OF CHROMATIN REMODELING MACHINERY AS POTENTIAL TARGET FOR NEW PHARMACOLOGICAL TREATMENT THROUGH THE ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS. 2016 13 6062 25 THE DEVELOPMENTAL BASIS OF EPIGENETIC REGULATION OF HTR2A AND PSYCHIATRIC OUTCOMES. THE SEROTONIN RECEPTOR 5-HT2A (ENCODED BY HTR2A) IS AN IMPORTANT REGULATOR OF FETAL BRAIN DEVELOPMENT AND ADULT COGNITIVE FUNCTION. ENVIRONMENTAL SIGNALS THAT INDUCE EPIGENETIC CHANGES OF SEROTONIN RESPONSE GENES, INCLUDING HTR2A, HAVE BEEN IMPLICATED IN ADVERSE MENTAL HEALTH OUTCOMES. THE OBJECTIVE OF THIS PERSPECTIVE ARTICLE IS TO ADDRESS THE MEDICAL IMPLICATIONS OF HTR2A EPIGENETIC REGULATION, WHICH HAS BEEN ASSOCIATED WITH BOTH INFANT NEUROBEHAVIORAL OUTCOMES AND ADULT MENTAL HEALTH. ONGOING RESEARCH HAS IDENTIFIED A REGION OF THE HTR2A PROMOTER THAT HAS BEEN ASSOCIATED WITH A NUMBER OF MEDICAL OUTCOMES IN ADULTS AND INFANTS, INCLUDING BIPOLAR DISORDER, SCHIZOPHRENIA, CHRONIC FATIGUE SYNDROME, BORDERLINE PERSONALITY DISORDER, SUICIDALITY, AND NEUROBEHAVIORAL OUTCOMES. EPIGENETIC REGULATION OF HTR2A HAS BEEN STUDIED IN SEVERAL DIFFERENT TYPES OF TISSUES, INCLUDING THE PLACENTA. THE PLACENTA IS AN IMPORTANT SOURCE OF SEROTONIN DURING FETAL NEURODEVELOPMENT, AND PLACENTAL EPIGENETIC VARIATION OF HTR2A HAS BEEN ASSOCIATED WITH INFANT NEUROBEHAVIORAL OUTCOMES, WHICH MAY REPRESENT THE BASIS OF ADULT MENTAL HEALTH DISORDERS. FURTHER ANALYSIS IS NEEDED TO IDENTIFY INTRINSIC AND EXTRINSIC FACTORS THAT MODULATE HTR2A METHYLATION, AND THE MECHANISM BY WHICH THIS EPIGENETIC VARIATION INFLUENCES FETAL GROWTH AND LEADS TO ALTERED BRAIN DEVELOPMENT, MANIFESTING IN PSYCHIATRIC DISORDERS. 2014 14 2874 22 FUNCTIONAL NUTRITION AS INTEGRATED INTERVENTION FOR IN- AND OUTPATIENT WITH SCHIZOPHRENIA. SCHIZOPHRENIA IS A CHRONIC AND PROGRESSIVE DISORDER CHARACTERIZED BY COGNITIVE, EMOTIONAL,AND BEHAVIORAL ABNORMALITIES ASSOCIATED WITH NEURONAL DEVELOPMENT AND SYNAPTIC PLASTICITY ALTERATIONS. GENETIC AND EPIGENETIC ABNORMALITIES IN CORTICAL PARVALBUMIN-POSITIVE GABAERGIC INTERNEURONS AND CONSEQUENT ALTERATIONS IN GLUTAMATE-MEDIATED EXCITATORY NEUROTRANSMISSION DURING EARLY NEURODEVELOPMENT UNDERLIE SCHIZOPHRENIA MANIFESTATION AND PROGRESSION. ALSO, EPIGENETIC ALTERATIONS DURING PREGNANCY OR EARLY PHASES OF POSTNATAL LIFE ARE ASSOCIATED WITH SCHIZOPHRENIA VULNERABILITY AND IN-FLAMMATORY PROCESSES, WHICH ARE AT THE BASIS OF BRAIN PATHOLOGY AND A HIGHER RISK OF COMORBIDITIES, INCLUDING CARDIOVASCULAR DISEASES AND METABOLIC SYNDROME. IN ADDITION, SCHIZOPHRENIA PATIENTS ADOPT AN UNHEALTHY LIFESTYLE AND POOR NUTRITION, LEADING TO PREMATURE DEATH. HERE, I EXPLORED THE ROLE OF FUNCTIONAL NUTRITION AS AN INTEGRATED INTERVENTION FOR THE LONG-TERM MANAGEMENT OF PATIENTS WITH SCHIZOPHRENIA. SEVERAL NATURAL BIOACTIVE COMPOUNDS IN PLANT-BASED WHOLE FOODS, INCLUDING FLAVONOIDS, PHYTONUTRIENTS, VITAMINS, FATTY ACIDS, AND MINERALS, MODULATE BRAIN FUNCTIONING BY TARGETING NEUROINFLAMMATION AND IMPROVING COGNITIVE DECLINE. ALTHOUGH FURTHER CLINICAL STUDIES ARE NEEDED, A FUNCTIONAL DIET RICH IN NATURAL BIOACTIVE COMPOUNDS MIGHT BE EFFECTIVE IN SYNERGISM WITH STANDARD TREATMENTS TO IMPROVE SCHIZOPHRENIA SYMPTOMS AND REDUCE THE RISK OF COMORBIDITIES. 2023 15 119 20 A SYSTEMATIC EXAMINATION OF BRAIN VOLUMETRIC ABNORMALITIES IN RECENT-ONSET SCHIZOPHRENIA USING VOXEL-BASED, SURFACE-BASED AND REGION-OF-INTEREST-BASED MORPHOMETRIC ANALYSES. BACKGROUND: BRAIN MORPHOMETRIC ABNORMALITIES IN SCHIZOPHRENIA HAVE BEEN EXTENSIVELY REPORTED IN THE LITERATURE. WHOLE-BRAIN VOLUMETRIC REDUCTIONS ARE ALMOST UNIVERSALLY REPORTED BY MOST STUDIES IRRESPECTIVE OF THE CHARACTERISTICS OF THE SAMPLES STUDIED (E.G., CHRONIC/RECENT-ONSET; MEDICATED/NEUROLEPTIC-NAIVE ETC.). HOWEVER, THE SAME CANNOT BE SAID OF THE REPORTED REGIONAL MORPHOMETRIC ABNORMALITIES IN SCHIZOPHRENIA. WHILE CERTAIN REGIONAL MORPHOMETRIC ABNORMALITIES ARE MORE FREQUENTLY REPORTED THAN OTHERS, THERE ARE NO SUCH ABNORMALITIES THAT ARE UNIVERSALLY REPORTED ACROSS STUDIES. VARIABILITY OF SOCIO-DEMOGRAPHIC AND CLINICAL CHARACTERISTICS ACROSS STUDY SAMPLES AS WELL AS TECHNICAL AND METHODOLOGICAL ISSUES RELATED TO ACQUISITION AND ANALYSES OF BRAIN STRUCTURAL IMAGES MAY CONTRIBUTE TO INCONSISTENCY OF BRAIN MORPHOMETRIC FINDINGS IN SCHIZOPHRENIA. THE OBJECTIVE OF THE PRESENT STUDY THEREFORE WAS TO SYSTEMATICALLY EXAMINE BRAIN MORPHOMETRY IN PATIENTS WITH RECENT-ONSET SCHIZOPHRENIA TO FIND OUT IF THERE ARE SIGNIFICANT WHOLE-BRAIN OR REGIONAL VOLUMETRIC DIFFERENCES DETECTABLE AT THE APPROPRIATE SIGNIFICANCE THRESHOLD, AFTER ATTEMPTING TO CONTROL FOR VARIOUS CONFOUNDING FACTORS THAT COULD IMPACT BRAIN VOLUMES. METHODS: STRUCTURAL MAGNETIC RESONANCE IMAGES OF 90 SUBJECTS (SCHIZOPHRENIA = 45; HEALTHY SUBJECTS = 45) WERE ACQUIRED USING A 3 TESLA MAGNET. MORPHOMETRIC ANALYSES WERE CARRIED OUT FOLLOWING STANDARD ANALYSES PIPELINES OF THREE MOST COMMONLY USED STRATEGIES, VIZ., WHOLE-BRAIN VOXEL-BASED MORPHOMETRY, WHOLE-BRAIN SURFACE-BASED MORPHOMETRY, AND BETWEEN-GROUP COMPARISONS OF REGIONAL VOLUMES GENERATED BY AUTOMATED SEGMENTATION AND PARCELLATION. RESULTS: IN OUR SAMPLE OF PATIENTS HAVING RECENT-ONSET SCHIZOPHRENIA WITH LIMITED NEUROLEPTIC EXPOSURE, THERE WERE NO SIGNIFICANT WHOLE BRAIN OR REGIONAL BRAIN MORPHOMETRIC ABNORMALITIES NOTED AT THE APPROPRIATE STATISTICAL SIGNIFICANCE THRESHOLDS WITH OR WITHOUT INCLUDING AGE, GENDER AND INTRACRANIAL VOLUME OR TOTAL BRAIN VOLUME IN THE STATISTICAL ANALYSES. CONCLUSIONS: IN THE BACKGROUND OF THE CONFLICTING FINDINGS IN THE LITERATURE, OUR FINDINGS INDICATE THAT BRAIN MORPHOMETRIC ABNORMALITIES MAY NOT BE DIRECTLY RELATED TO THE SCHIZOPHRENIA PHENOTYPE. ANALYSIS OF THE REASONS FOR THE INCONSISTENT RESULTS ACROSS STUDIES AS WELL AS CONSIDERATION OF ALTERNATE SOURCES OF VARIABILITY OF BRAIN MORPHOLOGY IN SCHIZOPHRENIA SUCH AS EPISTATIC AND EPIGENETIC MECHANISMS COULD PERHAPS ADVANCE OUR UNDERSTANDING OF STRUCTURAL BRAIN ALTERATIONS IN SCHIZOPHRENIA. 2015 16 6292 24 THE PRIMACY OF PSYCHOANALYTIC INTERVENTION IN RECOVERY FROM THE PSYCHOSES AND SCHIZOPHRENIAS. FUNCTIONAL CAPACITIES, SUCH AS ATTACHMENT AND AFFECT REGULATION, OBJECT RELATIONS CAPACITY, SYMBOLIC FUNCTION AND LANGUAGE DEVELOPMENT, NOW DOCUMENTED BY NEUROSCIENTIFIC RESEARCH AND EPIGENETICS, ARE REVIEWED. RESULTS FROM THIS RESEARCH, TOGETHER WITH OTHER FACTORS, ARE POSITED TO HAVE CONTRIBUTED TO EFFECTIVE CONTEMPORARY PSYCHOANALYTIC AND PSYCHOTHERAPEUTIC TREATMENTS FOR THE PSYCHOSES AND SCHIZOPHRENIAS. ETIOLOGICAL FACTORS INVOLVING THE SCHIZOPHRENIAS AND OTHER PSYCHOSES ARE CONSIDERED BOTH IN TERMS OF AN EPIGENETIC MODEL, AND IN TERMS OF HOW ETIOLOGY MAY, OR MAY NOT, AFFECT CLINICAL TREATMENT. THE LACANIAN 388 PROGRAM IS REVIEWED IN SOME DETAIL, AS ARE SEVERAL PSYCHOANALYTIC AND PSYCHOTHERAPEUTIC CLINICAL APPROACHES USED WITH THIS POPULATION OVER THE LAST SIX DECADES. ALL TREATMENTS FOCUS ON THE PRIMACY OF PSYCHOTHERAPEUTIC INTERVENTION, AND USE MEDICATIONS MINIMALLY, NOT AT ALL, OR ONLY AS INFORMED BY AN OVER-ARCHING PSYCHODYNAMIC MODEL OF TREATMENT. THE AUTHOR ARGUES THAT THERE IS NOW SUBSTANTIAL RESEARCH AND OUTCOME DATA SUGGESTING THAT THE PSYCHOSES AND SCHIZOPHRENIAS ARE NOT CHRONIC DETERIORATING CONDITIONS. RECOVERY IS OBSERVED IN MANY PSYCHOTIC AND SCHIZOPHRENIC PATIENTS TREATED WITH APPROACHES THAT FOCUS ON THE PRIMACY OF PSYCHOTHERAPEUTIC INTERVENTION. 2007 17 6184 26 THE IMPACT OF ENVIRONMENTAL FACTORS IN SEVERE PSYCHIATRIC DISORDERS. DURING THE LAST DECADES, SCHIZOPHRENIA HAS BEEN REGARDED AS A DEVELOPMENTAL DISORDER. THE NEURODEVELOPMENTAL HYPOTHESIS PROPOSES SCHIZOPHRENIA TO BE RELATED TO GENETIC AND ENVIRONMENTAL FACTORS LEADING TO ABNORMAL BRAIN DEVELOPMENT DURING THE PRE- OR POSTNATAL PERIOD. FIRST DISEASE SYMPTOMS APPEAR IN EARLY ADULTHOOD DURING THE SYNAPTIC PRUNING AND MYELINATION PROCESS. META-ANALYSES OF STRUCTURAL MRI STUDIES REVEALING HIPPOCAMPAL VOLUME DEFICITS IN FIRST-EPISODE PATIENTS AND IN THE LONGITUDINAL DISEASE COURSE CONFIRM THIS HYPOTHESIS. APART FROM THE INFLUENCE OF RISK GENES IN SEVERE PSYCHIATRIC DISORDERS, ENVIRONMENTAL FACTORS MAY ALSO IMPACT BRAIN DEVELOPMENT DURING THE PERINATAL PERIOD. SEVERAL ENVIRONMENTAL FACTORS SUCH AS ANTENATAL MATERNAL VIRUS INFECTIONS, OBSTETRIC COMPLICATIONS ENTAILING HYPOXIA AS COMMON FACTOR OR STRESS DURING NEURODEVELOPMENT HAVE BEEN IDENTIFIED TO PLAY A ROLE IN SCHIZOPHRENIA AND BIPOLAR DISORDER, POSSIBLY CONTRIBUTING TO SMALLER HIPPOCAMPAL VOLUMES. IN MAJOR DEPRESSION, PSYCHOSOCIAL STRESS DURING THE PERINATAL PERIOD OR IN ADULTHOOD IS AN IMPORTANT TRIGGER. IN ANIMAL STUDIES, CHRONIC STRESS OR REPEATED ADMINISTRATION OF GLUCOCORTICOIDS HAVE BEEN SHOWN TO INDUCE DEGENERATION OF GLUCOCORTICOID-SENSITIVE HIPPOCAMPAL NEURONS AND MAY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF AFFECTIVE DISORDERS. EPIGENETIC MECHANISMS ALTERING THE CHROMATIN STRUCTURE SUCH AS HISTONE ACETYLATION AND DNA METHYLATION MAY MEDIATE EFFECTS OF ENVIRONMENTAL FACTORS TO TRANSCRIPTIONAL REGULATION OF SPECIFIC GENES AND BE A PROMINENT FACTOR IN GENE-ENVIRONMENTAL INTERACTION. IN ANIMAL MODELS, GENE-ENVIRONMENTAL INTERACTION SHOULD BE INVESTIGATED MORE INTENSELY TO UNRAVEL PATHOPHYSIOLOGICAL MECHANISMS. THESE FINDINGS MAY LEAD TO NEW THERAPEUTIC STRATEGIES INFLUENCING EPIGENETIC TARGETS IN SEVERE PSYCHIATRIC DISORDERS. 2014 18 881 21 CHRONIC CLOZAPINE TREATMENT RESTRAINS VIA HDAC2 THE PERFORMANCE OF MGLU2 RECEPTOR AGONISM IN A RODENT MODEL OF ANTIPSYCHOTIC ACTIVITY. PRECLINICAL FINDINGS IN RODENT MODELS POINTED TOWARD ACTIVATION OF METABOTROPIC GLUTAMATE 2/3 (MGLU2/3) RECEPTORS AS A NEW PHARMACOLOGICAL APPROACH TO TREAT PSYCHOSIS. HOWEVER, MORE RECENT STUDIES FAILED TO SHOW CLINICAL EFFICACY OF MGLU2/3 RECEPTOR AGONISM IN SCHIZOPHRENIA PATIENTS. WE PREVIOUSLY PROPOSED THAT LONG-TERM ANTIPSYCHOTIC MEDICATION RESTRICTED THE THERAPEUTIC EFFECTS OF THESE GLUTAMATERGIC AGENTS. HOWEVER, LITTLE IS KNOWN ABOUT THE MOLECULAR MECHANISM UNDERLYING THE POTENTIAL REPERCUSSION OF PREVIOUS ANTIPSYCHOTIC EXPOSURE ON THE THERAPEUTIC PERFORMANCE OF MGLU2/3 RECEPTOR AGONISTS. HERE WE SHOW THAT THIS MALADAPTIVE EFFECT OF ANTIPSYCHOTIC TREATMENT IS MEDIATED MOSTLY VIA HISTONE DEACETYLASE 2 (HDAC2). CHRONIC TREATMENT WITH THE ANTIPSYCHOTIC CLOZAPINE LED TO A DECREASE IN MOUSE FRONTAL CORTEX MGLU2 MRNA, AN EFFECT THAT REQUIRED EXPRESSION OF BOTH HDAC2 AND THE SEROTONIN 5-HT(2A) RECEPTOR. THIS TRANSCRIPTIONAL ALTERATION OCCURRED IN ASSOCIATION WITH HDAC2-DEPENDENT REPRESSIVE HISTONE MODIFICATIONS AT THE MGLU2 PROMOTER. WE FOUND THAT CHRONIC CLOZAPINE TREATMENT DECREASED VIA HDAC2 THE CAPABILITIES OF THE MGLU2/3 RECEPTOR AGONIST LY379268 TO ACTIVATE G-PROTEINS IN THE FRONTAL CORTEX OF MICE. CHRONIC CLOZAPINE TREATMENT BLUNTED THE ANTIPSYCHOTIC-RELATED BEHAVIORAL EFFECTS OF LY379268, AN EFFECT THAT WAS NOT OBSERVED IN HDAC2 KNOCKOUT MICE. MORE IMPORTANTLY, CO-ADMINISTRATION OF THE CLASS I AND II HDAC INHIBITOR SAHA (VORINOSTAT) PRESERVED THE ANTIPSYCHOTIC PROFILE OF LY379268 AND FRONTAL CORTEX MGLU2/3 RECEPTOR DENSITY IN WILD-TYPE MICE. THESE FINDINGS RAISE CONCERNS ON THE DESIGN OF PREVIOUS CLINICAL STUDIES WITH MGLU2/3 AGONISTS, PROVIDING THE RATIONALE FOR THE DEVELOPMENT OF HDAC2 INHIBITORS AS A NEW EPIGENETIC-BASED APPROACH TO IMPROVE THE CURRENTLY LIMITED RESPONSE TO TREATMENT WITH GLUTAMATERGIC ANTIPSYCHOTICS. 2019 19 4828 25 OLANZAPINE INDUCED DNA METHYLATION CHANGES SUPPORT THE DOPAMINE HYPOTHESIS OF PSYCHOSIS. BACKGROUND: THE DOPAMINE (DA) HYPOTHESIS OF SCHIZOPHRENIA PROPOSES THE MENTAL ILLNESS IS CAUSED BY EXCESSIVE TRANSMISSION OF DOPAMINE IN SELECTED BRAIN REGIONS. MULTIPLE LINES OF EVIDENCE, INCLUDING BLOCKAGE OF DOPAMINE RECEPTORS BY ANTIPSYCHOTIC DRUGS THAT ARE USED TO TREAT SCHIZOPHRENIA, SUPPORT THE HYPOTHESIS. HOWEVER, THE DOPAMINE D2 RECEPTOR (DRD2) BLOCKADE CANNOT EXPLAIN SOME IMPORTANT ASPECTS OF THE THERAPEUTIC EFFECT OF ANTIPSYCHOTIC DRUGS. IN THIS STUDY, WE HYPOTHESIZED THAT ANTIPSYCHOTIC DRUGS COULD AFFECT THE TRANSCRIPTION OF GENES IN THE DA PATHWAY BY ALTERING THEIR EPIGENETIC PROFILE. METHODS: TO TEST THIS HYPOTHESIS, WE EXAMINED THE EFFECT OF OLANZAPINE, A COMMONLY USED ATYPICAL ANTIPSYCHOTIC DRUG, ON THE DNA METHYLATION STATUS OF GENES FROM DA NEUROTRANSMISSION IN THE BRAIN AND LIVER OF RATS. GENOMIC DNA ISOLATED FROM HIPPOCAMPUS, CEREBELLUM, AND LIVER OF OLANZAPINE TREATED (N = 2) AND CONTROL (N = 2) RATS WERE ANALYZED USING RAT SPECIFIC METHYLATION ARRAYS. RESULTS: OUR RESULTS SHOW THAT OLANZAPINE CAUSES METHYLATION CHANGES IN GENES ENCODING FOR DA RECEPTORS (DOPAMINE D1 RECEPTOR, DOPAMINE D2 RECEPTOR AND DOPAMINE D5 RECEPTOR), A DA TRANSPORTER (SOLUTE CARRIER FAMILY 18 MEMBER 2), A DA SYNTHESIS (DIFFERENTIAL DISPLAY CLONE 8), AND A DA METABOLISM (CATECHOL-O-METHYLTRANSFERASE). WE ASSESSED A TOTAL OF 40 GENES IN THE DA PATHWAY AND FOUND 19 TO BE DIFFERENTIALLY METHYLATED BETWEEN OLANZAPINE TREATED AND CONTROL RATS. MOST (17/19) GENES SHOWED AN INCREASE IN METHYLATION, IN THEIR PROMOTER REGIONS WITH IN SILICO ANALYSIS STRONGLY INDICATING A FUNCTIONAL POTENTIAL TO SUPPRESS TRANSCRIPTION IN THE BRAIN. CONCLUSION: OUR RESULTS SUGGEST THAT CHRONIC OLANZAPINE MAY REDUCE DA ACTIVITY BY ALTERING GENE METHYLATION. IT MAY ALSO EXPLAIN THE DELAYED THERAPEUTIC EFFECT OF ANTIPSYCHOTICS, WHICH OCCURS DESPITE RAPID DOPAMINE BLOCKADE. FURTHERMORE, GIVEN THE COMMON NATURE OF EPIGENETIC VARIATION, THIS LENDS INSIGHT INTO THE DIFFERENTIAL THERAPEUTIC RESPONSE OF PSYCHOTIC PATIENTS WHO DISPLAY ADEQUATE BLOCKAGE OF DOPAMINE RECEPTORS. 2013 20 6897 17 [TELOMERE-TELOMERASE SYSTEM IN AGING, NORM AND PATHOLOGY (LITERATURE REVIEW)]. THIS LITERATURE REVIEW PRESENTS RESULTS OF RESEARCH SHOWING ASSOCIATION BETWEEN FUNCTIONAL ACTIVITY OF THE TELOMERE-TELOMERASE SYSTEM AND MENTAL COGNITIVE AND EMOTIONAL PROCESSES IN NORMAL AND VARIOUS PATHOLOGICAL STATES: CHRONIC STRESS, DEPRESSION, BIPOLAR DISORDER, SCHIZOPHRENIA, MILD COGNITIVE IMPAIRMENT AND DEMENTIA IN AGING. IT ALSO REFERS TO AGE-SPECIFIC, PSYCHO-SOCIAL, ECONOMIC, IMMUNOLOGICAL, GENETIC AND EPIGENETIC FACTORS THAT INFLUENCE THESE RELATIONSHIPS. 2017