•Sex influenced the extent to differences in mRNAs in lymphocytes (PBLs) between schizophrenics (CSZ) and controls (NPC). There were differences between in CSZ vs NPC among males but not females.•In ...PBLs of males DNMT1 and DMNT3A mRNAs in of CSZ were higher in than in NPC. This corresponded to higher levels of DNMT1 in the post mortem brain samples of CSZ.•Although GABAergic GAD67 mRNA was lower in post-mortem brain samples of CSZ vs NPC, in PBLs GABAergic mRNAs were higher in CSZ than NPC.•Treatment with clozapine significantly affected the levels of several mRNAs in PBLs of CSZ and treatment with clozapine explained most of the difference in mRNAs between CSZ vs NPC in these mRNAs.
Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis. In parallel we studied DNMT1 and GAD67 in samples of brain tissues from 19 CSZ, 26 NPC. In PBLs DNMT1 and DNMT3A mRNA levels were significantly higher in male CSZ vs NPC No significant differences were detected in females. The GAD1, NR3C1 and CNTNAP2 mRNA levels were significantly higher in CSZ than NPC. In CSZ patients treated with clozapine, GAD-1 related, CNTNAP2, and IMPA2 mRNAs were significantly higher than in CSZ subjects not treated with clozapine. Differences between CSZ vs NPC in these mRNAs was primarily attributable to the clozapine treatment. In the brain samples, DNMT1 was significantly higher and GAD67 was significantly lower in CSZ than in NPC, but there were no significant sex differences in diagnostic effects. These findings highlight the importance of considering sex and drug treatment effects in assessing the substantive significance of differences in mRNAs between CSZ and NPC.
Suicide is a major public health concern; nevertheless, its neurobiology remains unknown. An area of interest in suicide research is the dorsolateral prefrontal cortex (DLPFC). We aimed to identify ...altered proteins and potential biological pathways in the DLPFC of individuals who died by suicide employing mass spectrometry-based untargeted proteomics. Postmortem DLPFC from age-matched male suicide mood disorder cases (n = 5) and non-suicide mood disorder cases (n = 5) were compared. The proteins that differed between groups at false discovery rate (FDR) adjusted p-values (Benjamini-Hochberg-Yekutieli) <0.3 and Log
fold change (FC) >|0.4| were considered statistically significant and were subjected to pathway analysis by Qiagen Ingenuity software. Thirty-three of the 5162 detected proteins showed significantly altered expression levels in the suicide cases and two of them after adjustment for body mass index. The top differentially expressed protein was potassium voltage-gated channel subfamily Q member 3 (KCNQ3) (Log
FC = -0.481,
= 2.10 × 10
, FDR = 5.93 × 10
), which also showed a trend to downregulation in Western blot (
= 0.045, Bonferroni adjusted p = 0.090). The most notably enriched pathway was the GABA receptor signaling pathway (
< 0.001). Here, we report a reduction trend of KCNQ3 levels in the DLPFC of male suicide victims with mood disorders. Further studies with a larger sample size and equal sex representation are needed.
The polygenic nature of complex psychiatric disorders suggests a common pathway that may be involved in the down-regulation of multiple genes through an epigenetic mechanism. To investigate the role ...of methylation in down-regulating the expression of mRNAs that may be associated with the schizophrenia phenotype, we have adopted a cell-culture model amenable to this line of investigation. We have administered methionine (2 mM) to primary cultures of cortical neurons prepared from embryonic day 16 mice and show that this treatment down-regulated reelin and glutamic acid decarboxylase 67 (GAD67) mRNA expression but not that corresponding to neuron-specific enolase mRNA. Moreover, methionine increased methylation of the reelin promoter, suggesting a possible mechanism for the observed change. These cultures contain a mixed population of neurons and glia. Approximately 83% of the neurons are GABAergic based on GAD immunoreactivity, and these neurons coexpress high levels of reelin and DNA methyltransferase (Dnmt) 1 immunoreactivity. To examine whether Dnmt1 regulates reelin gene expression, we used an antisense approach to reduce (knock down) Dnmt1 expression. The reduced Dnmt1 mRNA and protein were accompanied by increased reelin mRNA expression. More importantly, the Dnmt1 knockdown blocked the methionine-induced reelin and GAD67 mRNA down-regulation. These data support the hypothesis that the reduced amounts of reelin and GAD67 mRNAs documented in postmortem schizophrenia brain may be the consequence of a Dnmt1-mediated hypermethylation of the corresponding promoters.
Pharmacogenomic testing, specifically for pharmacokinetic (PK) and pharmacodynamic (PD) genetic variation, may contribute to a better understanding of baseline genetic differences in patients seeking ...treatment for depression, which may further impact clinical antidepressant treatment recommendations. This study evaluated PK and PD genetic variation and the clinical use of such testing in treatment seeking patients with bipolar disorder (BP) and major depressive disorder (MDD) and history of multiple drug failures/treatment resistance.
Consecutive depressed patients evaluated at the Mayo Clinic Depression Center over a 10-year study time frame (2003-2013) were included in this retrospective analysis. Diagnoses of BP or MDD were confirmed using a semi-structured diagnostic interview. Clinical rating scales included the Hamilton Rating Scale for Depression (HRSD
), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Adverse Childhood Experiences (ACE) Questionnaire. Clinically selected patients underwent genotyping of cytochrome P450
/
and the serotonin transporter
. PK and PD differences and whether clinicians incorporated test results in providing recommendations were compared between the two patient groups.
Of the 1795 patients, 167/523 (31.9%) with BP and 446/1272 (35.1%) with MDD were genotyped. Genotyped patients had significantly higher self-report measures of depression and anxiety compared to non-genotyped patients. There were significantly more
poor metabolizer (PM) phenotypes in BP (9.3%) vs. MDD patients (1.7%,
= 0.003); among participants with an S-allele, the rate of
PM phenotype was even higher in the BP (9.8%) vs. MDD (0.6%,
= 0.003). There was a significant difference in the distribution of
genotypes between BP (
= 28.1%,
= 59.3%,
= 12.6%) and MDD (
= 31.4%,
= 46.1%,
= 22.7%) patients (
< 0.01).
There may be underlying pharmacogenomic differences in treatment seeking depressed patients that potentially have impact on serum levels of
metabolized antidepressants (i.e., citalopram / escitalopram) contributing to rates of efficacy vs. side effect burden with additional potential risk of antidepressant response vs. induced mania. The evidence for utilizing pharmacogenomics-guided therapy in MDD and BP is still developing with a much needed focus on drug safety, side effect burden, and treatment adherence.
In this review, we discuss changes in the regulation of gene expression in the central nervous system (CNS) associated with DNA (cytosine-5) methylation, chromatin remodeling and post-translational ...covalent modifications of histones.
During brain development, abnormal intrinsic or extrinsic cues may compromise epigenetic processes regulating neural stem cell proliferation and differentiation and thus directly or indirectly could contribute to altered epiphenotypes leading to psychiatric disorders. These mechanisms, that include chromatin remodeling and reversible changes in promoter methylation patterns, are largely expressed by terminally differentiated cortical GABAergic neurons. These neurons are unique among various brain cell subtypes because they express high levels of DNA-methyltransferase-1 (DNMT1). Moreover, DNMT1 expression is further increased in schizophrenia (SZ) and bipolar (BP) disorder brains.
To unravel how this pathological DNMT1 overexpression induces GABAergic neuronal dysfunction in SZ and in other psychoses, we report on how alterations in methylation modify the expression of susceptible vulnerability genes such as reelin or GAD67 in these neurons. The results encourage the view that promoter hypermethylation in GABAergic neurons that occurs in SZ represents a testable target for novel therapeutic strategies to treat this disorder.
Bipolar disorder (BD) is a highly heritable disease, with genetic influences explaining 60–85% of the risk. Clinical presentation is heterogeneous, often co-occurring with other mental illnesses and ...medical conditions. To better understand its pathophysiology, BD has been conceptualized in multiple sub-phenotypes with diverse clinical characteristics and courses of illness. Although BD type I (BDI) and type II (BDII) are the most widely recognized sub-phenotypes, others such as BD with psychosis, suicidality, and early onset, can also be encompassed within this term. There is evidence to suggest that BD sub-phenotypes might be partly genetically determined. Hence, polygenic risk scores (PRSs) for various diseases and traits have been tested for their association with BD sub-phenotypes. We aimed to review the studies investigating the association between diverse PRSs and BD sub-phenotypes.
We conducted a systematic review following the PRISMA 2020 statement (PROSPERO CRD42022377199). Medline, Cochrane, Embase, Scopus, and Web of Science databases were searched in October 2022 for the terms “bipolar disorder”, “polygenic risk score” and “sub-phenotype”. Title, abstract and full-text screening, data extraction, and risk of bias assessment were conducted by two reviewers independently. Disagreements were solved by consensus and discussion with a senior researcher. We verified that no two studies investigating the same sub-phenotype shared both base and target samples, ensuring that the consistency of the findings was not overestimated.
From 1,248 records, 20 studies met inclusion criteria. The majority of the studies had a low risk of bias. Only 2 included subjects of non-European ancestries. The most frequently tested PRSs were for schizophrenia (SCZ, n=17), BD (n=14), and major depressive disorder (MDD, n=9). The most studied sub-phenotypes were psychosis (n=9), BD subtype BDI, BDII, schizoaffective disorder, bipolar type (SABD) (n=5), age at onset (n=5), and suicide attempt (SA, n=4). Overall, the most consistent association was observed between a higher SCZ-PRS and BD with psychosis, especially with mood-incongruent symptoms. SCZ-PRS was the highest in SABD, followed by BDI, and lowest in BDII. The absence of an association between early onset BD and BD PRS or MDD PRS was consistent across studies. Associations between various PRSs and SA had mixed findings.
Our findings suggest an association between an increased genetic risk for SCZ and a severity spectrum in BD, starting from SABD, followed by BD I and BD II sub-phenotypes. BD with psychosis, especially with mood-incongruent symptoms, seems to be the main driver of this finding. This is in line with previous substantial evidence for partial polygenic overlap of SCZ and BD. Current evidence up to this point did not demonstrate an association between any other studied PRS and BD sub-phenotype. Contrary to our expectations, a greater polygenic load for BD does not seem to be related to earlier BD onset, nor does a higher MDD PRS correlate with suicide attempts to this point. Overall, our results point towards BD sub-phenotypes having different polygenic contributors, which are sometimes shared with other psychiatric diseases. An important limitation of the findings is the strong Eurocentric bias present in PRS analysis studies, highlighting a need for including more ancestrally diverse populations in such studies.
•Antidepressants and other neuropsychiatric medications differentially influence mitochondrial function.•Specific antidepressants and other neuropsychiatric medications have negative effects on ...mitochondria.•Most antidepressants and other neuropsychiatric medications showed positive or mixed effects on mitochondrial function.
Individuals with mitochondrial disease often present with psychopathological comorbidity, and mitochondrial dysfunction has been proposed as the underlying pathobiology in various psychiatric disorders. Several studies have suggested that medications used to treat neuropsychiatric disorders could directly influence mitochondrial function. This review provides a comprehensive overview of the effect of these medications on mitochondrial function. We collected preclinical information on six major groups of antidepressants and other neuropsychiatric medications and found that the majority of these medications either positively influenced mitochondrial function or showed mixed effects. Only amitriptyline, escitalopram, and haloperidol were identified as having exclusively adverse effects on mitochondrial function. In the absence of formal clinical trials, and until such trials are completed, the data from preclinical studies reported and discussed here could inform medication prescribing practices for individuals with psychopathology and impaired mitochondrial function in the underlying pathology.
Psychiatric disorders differ in their prevalence, symptom profiles, and disease courses in men and women. However, sex differences in psychiatric disorders have not received enough attention to guide ...treatment recommendations. This systematic review aims to summarize sex differences in the treatment responses and adverse effects of mood stabilizers and antipsychotics transdiagnostically.
We conducted a systematic review following the PRISMA 2020 statement (CRD42020212478). A literature search was conducted using MEDLINE, Embase, Cochrane Central, PsycINFO, Web of Science Core Collection, and Scopus databases. Studies comparing mood stabilizer or antipsychotic treatment outcomes in men and women were included. JBI critical appraisal checklists were used to assess bias risk.
Out of 4866 records, 129 reports (14 on mood stabilizers, 115 on antipsychotics) with varying designs were included. Sample sizes ranged from 17 to 22,774 participants (median = 147). The most common psychiatric diagnoses were schizophrenia spectrum (n = 109, 84.5 %) and bipolar disorders (n = 38, 29.5 %). Only four studies explored sex differences in mood stabilizer treatment response. In 40 articles on antipsychotic treatment response, 18 indicated no sex difference, while 16 showed females had better outcomes. Women had more adverse effects with both mood stabilizers and antipsychotics. The risk of bias was low in 84 (65.1 %) of studies.
Substantial heterogeneity among the studies precluded performing a meta-analysis.
Number of studies focusing on sex differences in treatment outcomes of mood stabilizers is limited. Women may respond better to antipsychotics than men, but also experience more side effects. The impact of pharmacokinetics on sex differences warrants more attention.
•Antipsychotic treatment response appears to differ by sex, possibly favoring women.•There is limited research on sex differences in mood stabilizer response.•Women experience more adverse effects with mood stabilizers and antipsychotics.•Hypothyroidism with lithium is more common in women.•Women using antipsychotics have more weight gain/obesity and hyperprolactinemia.
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