Velo-Cardio-Facial Syndrome

Velocardiofacial syndrome (VCFS), also known as DiGeorge, conotruncal anomaly face, and Cayler syndromes, is caused by a microdeletion in the long arm of Chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the microdeletion region and the physical and neuropsychiatric phenotype of the syndrome. Velocardiofacial syndrome has a wide spectrum of more than 200 physical manifestations including palate and cardiac anomalies. Yet, the most challenging manifestations of VCFS are the learning disabilities and neuropsychiatric disorders. As VCFS is relatively common and as up to one third of the participants with VCFS develop schizophrenia-like psychotic disorder, the syndrome is the most commonly known genetic risk factor to schizophrenia. Identifying the genetic, cognitive, and psychiatric risk factors for VCFS-schizophrenia is under the focus of intensive research

18 kDa Translocator Protein in Mitochondria-Related Pathology: The Case of Traumatic Brain Injury

Translocator protein (TSPO) takes part in mitochondrial adenine triphosphate (ATP) production and transport. Mitochondrial TSPO is a part of the apoptotic and cell necrotic mechanism. Ligands to TSPO, endogenous and synthetic, have different effects on metabolism and protein expression in human well-differentiated metabolically active cells. In general, most of the TSPO ligands affect the cellular function or metabolism in the same general direction, but different specific TSPO ligands have their own unique effects in human cells. Regulation of gene expression via the actions of TSPO ligands on the mitochondrial TSPO may form an essential mechanism for the regulation of cellular functions, especially during acute organ injury, such as acute brain damage. The exact mode of action of the specific TSPO ligands is not clear enough and should be further investigated. TSPO is a potential target for therapeutic efforts to mitigate secondary tissue injury caused by programmed cell death

Distinct Response Inhibition Patterns in Obsessive Compulsive Disorder Patients and Pathological Gamblers

Background: Obsessive-compulsive disorder (OCD) and pathological gambling (PG) are common disorders. The cognitive models of OCD and PG focus on abnormalities in response inhibition. Although, these functions have been studied in different PG and OCD samples, no study has compared the response inhibition in both.Methods: Medication-naïve OCD (n = 61) and PG subjects (n = 109) and healthy controls (n = 131) performed CPT and Go/NoGo tasks.Results: Compared to healthy controls (HC), PG and OCD groups underperformed on speed and exhibited larger time variability on the CPT and Go/NoGo task. Only in OCD patients, a positive correlation between omission errors and response time (RT) was observed in the CPT. At the Go/NoGo task, a negative correlation between false alarms and RT (a fast-errors trade-off) was significant only in the PG group. The HC group had greater sensitivity values (d') than the OCD and PG groups in the Go/NoGo task. The PG group displayed lower d' values and more conservative response criterion in the CPT. In addition, only the OCD group expressed a high switching cost compared to both the PG and HC groups in terms of the RT and d' values.Conclusions: Both the PG and OCD groups demonstrated impaired response inhibition compared to the HC group. On several measures, the OCD and PG groups showed comparable impairments, and in others these were distinct. Thus, it appears that distinct neurocognitive patterns are involved in performance of the CPT and the Go/NoGo tasks among OCD and PG subjects whose cognitive status is currently under intensive investigation

Alcohol metabolizing genes and alcohol phenotypes in an Israeli household sample

BACKGROUND: Alcohol dehydrogenase 1B and 1C (ADH1B and ADH1C) variants have been robustly associated with alcohol phenotypes in East Asian populations, but less so in non-Asian populations where prevalence of the most protective ADH1B allele is low (generally <5%). Further, the joint effects of ADH1B and ADH1C on alcohol phenotypes have been unclear. Therefore, we tested the independent and joint effects of ADH1B and ADH1C on alcohol phenotypes in an Israeli sample, with higher prevalence of the most protective ADH1B allele than other non-Asian populations. METHODS: A structured interview assessed lifetime drinking and alcohol use disorders (AUDs) in adult Israeli household residents. Four single nucleotide polymorphisms (SNPs) were genotyped: ADH1B (rs1229984, rs1229982, and rs1159918) and ADH1C (rs698). Regression analysis examined the association between alcohol phenotypes and each SNP (absence vs. presence of the protective allele) as well as rs698/rs1229984 diplotypes (also indicating absence or presence of protective alleles) in lifetime drinkers (n = 1,129). RESULTS: Lack of the ADH1B rs1229984 protective allele was significantly associated with consumption- and AUD-related phenotypes (OR = 1.77 for AUD; OR = 1.83 for risk drinking), while lack of the ADH1C rs698 protective allele was significantly associated with AUD-related phenotypes (OR = 2.32 for AUD). Diplotype analysis indicated that jointly ADH1B and ADH1C significantly influenced AUD-related phenotypes. For example, among those without protective alleles for ADH1B or ADH1C, OR for AUD was 1.87 as compared to those without the protective allele for ADH1B only and was 3.16 as compared to those with protective alleles for both ADH1B and ADH1C. CONCLUSIONS: This study adds support for the relationship of ADH1B and ADH1C and alcohol phenotypes in non-Asians. Further, these findings help clarify the mixed results from previous studies by showing that ADH1B and ADH1C jointly effect AUDs, but not consumption. Studies of the association between alcohol phenotypes and either ADH1B or ADH1C alone may employ an oversimplified model, masking relevant information

Alcohol consumption mediates the relationship between ADH1B and DSM-IV alcohol use disorder and criteria

OBJECTIVE: A single nucleotide variation in the alcohol dehydrogenase 1B (ADH1B) gene, rs1229984, produces an ADH1B enzyme with faster acetaldehyde production. This protective variant is associated with lower alcohol consumption and lower risk for alcohol use disorders (AUDs). Based on the premise that faster ADH1B kinetics decreases alcohol consumption, we formally tested if the association between ADH1B variant rs1229984 and AUDs occurs through consumption. We also tested whether the association between rs1229984 and each of the 11 Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), AUD criteria occurs through consumption. METHOD: A total of 1,130 lifetime drinkers from an Israeli household sample were assessed with a structured interview and genotyped for rs1229984 (protective allele frequency = 0.28). Logistic regression evaluated the association between rs1229984 and each phenotype (AUDs, 11 individual DSM-IV criteria). For phenotypes significantly related to rs1229984, the effect through consumption was tested with logistic regression and bootstrapping. RESULTS: ADH1B rs1229984 was significantly associated with AUDs and six criteria, with odds ratios ranging from 1.32 to 1.96. The effect through consumption was significant for these relationships, explaining 23%-74% of the total ADH1B effect. CONCLUSIONS: This is the first study to show that ADH1B rs1229984 is related to 6 of the 11 DSM-IV AUD criteria and that alcohol consumption explained a significant proportion of these associations and the association of ADH1B with AUDs. Better understanding of the relationship between ADH1B and the DSM-IV AUD criteria, including effects through consumption, will enhance our understanding of the etiologic model through which AUDs can occur

Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS. METHODS: The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment. RESULTS: Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS. CONCLUSIONS: Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS

A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention

Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n = 27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state

The Future of Child and Adolescent Clinical Psychopharmacology: A Systematic Review of Phase 2, 3, or 4 Randomized Controlled Trials of Pharmacologic Agents Without Regulatory Approval or for Unapproved Indications

The pace of development and implementation of novel medications in child and adolescent psychiatry has remained slow. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010 to 08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia. We also included RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥1 primary outcome, 43 (19%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes

The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010–08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes