Polymorphism of the 5-HT2A Receptor Gene: Association with Stress-Related Indices in Healthy Middle-Aged Adults

Past research has concentrated on the stress system and personality in order to explain the variance found in cognitive performance in old age. A growing body of research is starting to focus on genetic polymorphism as an individual difference factor to explain the observed heterogeneity in cognitive function. While the functional mechanism is still under investigation, polymorphism of the 5-HT2A receptor gene (−1438A/G) has been linked to certain behavioral and physiological outcomes, including cortisol secretion, the expression of certain personality traits, and memory performance. It was the goal of the present study to investigate the association between the −1438A/G polymorphism and stress hormone secretion, stress-related psychological measures, and cognitive performance in a group of adults between the ages of 50 and 65. To examine these associations, 101 middle-aged adults were recruited, completed a battery of psychological questionnaires and were administered a battery of cognitive tasks that assess frontal lobe and hippocampal function. Basal and stress-reactive salivary cortisol levels were collected, at home and in the laboratory. Analyses on psychological measures showed that participants with the GG genotype reported significantly higher levels of neuroticism compared to the AG group and higher levels of depression and more emotion-based coping strategies compared to both the AG and AA group. In terms of cortisol secretion, the AA genotype was related to a significantly higher awakening cortisol response (ACR) compared to the AG and GG group and the GG genotype group displayed a greater increase in cortisol secretion following a psychosocial stressor compared to the two other groups. On measures of cognitive performance, the AA genotype group performed significantly better on a test of declarative memory and selective attention compared to the other two groups. Together, these results suggest that carriers of the GG genotype are more susceptible to low mood and display a greater potential for an overactive stress system, which may influence cognitive function in later years

The effects of methylphenidate (Ritalin) on the neurophysiology of the monkey caudal prefrontal cortex

© 2019 Tremblay et al. Methylphenidate (MPH), commonly known as Ritalin, is the most widely prescribed drug worldwide to treat patients with attention deficit disorders. Although MPH is thought to modulate catecholamine neurotransmission in the brain, it remains unclear how these neurochemical effects influence neuronal activity and lead to attentional enhancements. Studies in rodents overwhelmingly point to the lateral prefrontal cortex (LPFC) as a main site of action of MPH. To understand the mechanism of action of MPH in a primate brain, we recorded the responses of neuronal populations using chronic multielectrode arrays implanted in the caudal LPFC of two macaque monkeys while the animals performed an attention task (N 2811 neuronal recordings). Over different recording sessions (N 55), we orally administered either various doses of MPH or a placebo to the animals. Behavioral analyses revealed positive effects of MPH on task performance at specific doses. However, analyses of individual neurons activity, noise correlations, and neuronal ensemble activity using machine learning algorithms revealed no effects of MPH. Our results suggest that the positive behavioral effects of MPH observed in primates (including humans) may not be mediated by changes in the activity of caudal LPFC neurons. MPH may enhance cognitive performance by modulating neuronal activity in other regions of the attentional network in the primate brain

From early intervention in psychosis to youth mental health reform: a review of the evolution and transformation of mental health services for young people.

PURPOSE: The objective of this review is to report on recent developments in youth mental health incorporating all levels of severity of mental disorders encouraged by progress in the field of early intervention in psychotic disorders, research in deficiencies in the current system and social advocacy. METHODS: The authors have briefly reviewed the relevant current state of knowledge, challenges and the service and research response across four countries (Australia, Ireland, the UK and Canada) currently active in the youth mental health field. RESULTS: Here we present information on response to principal challenges associated with improving youth mental services in each country. Australia has developed a model comprised of a distinct front-line youth mental health service (Headspace) to be implemented across the country and initially stimulated by success in early intervention in psychosis; in Ireland, Headstrong has been driven primarily through advocacy and philanthropy resulting in front-line services (Jigsaw) which are being implemented across different jurisdictions; in the UK, a limited regional response has addressed mostly problems with transition from child-adolescent to adult mental health services; and in Canada, a national multi-site research initiative involving transformation of youth mental health services has been launched with public and philanthropic funding, with the expectation that results of this study will inform implementation of a transformed model of service across the country including indigenous peoples. CONCLUSIONS: There is evidence that several countries are now engaged in transformation of youth mental health services and in evaluation of these initiatives.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00127-015-1165-

OA Lal 2023 Digital health innovation to prevent relapse and support recovery in young people with first-episode psychosis : A pilot study of Horyzons-Canada

Digital health innovations may help to improve access to psychosocial therapy and peer support; however, the existence of evidence-based digital health interventions for individuals recovering from a first-episode psychosis (FEP) remains limited. This study aims to investigate the feasibility, acceptability, safety, and pre-post outcomes of Horyzons-Canada (HoryzonsCa), a Canadian adaptation of a digital mental health intervention consisting of psychosocial interventions, online social networking, and clinical and peer support moderation. Using a convergent mixed-methods research design, we recruited participants from a specialized early intervention clinic for FEP in Montreal, Canada. Twenty-three participants (mean age = 26.8) completed baseline assessments, and 20 completed follow-up assessments after 8 weeks of intervention access. Most participants provided positive feedback on general experience (85%, 17/20) and the utility of Horyzons for identifying their strengths (70%, 14/20). Almost all perceived the platform as easy to use (95%, 19/20) and felt safe using it (90%, 18/20). There were no adverse events related to the intervention. Participants used HoryzonsCa to learn about their illness and how to get better (65%, 13/20), receive support (60%, 12/20), and access social networking (35%, 7/20) and peer support (30%, 6/20). Regarding adoption, 65% (13/20) logged in at least 4 times over 8 weeks. There was a nonsignificant increase in social functioning and no deterioration on the Clinical Global Impression Scale. Overall, HoryzonsCa was feasible to implement and perceived as safe and acceptable. More research is needed with larger sample sizes and using in-depth qualitative methods to better understand the implementation and impact of HoryzonsCa

Association study of the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia

BACKGROUND: Brahma (BRM) is a key component of the multisubunit SWI/SNF complex, a complex which uses the energy of ATP hydrolysis to remodel chromatin. BRM contains an N-terminal polyglutamine domain, encoded by a polymorphic trinucleotide (CAA/CAG) repeat, the only known polymorphism in the coding region of the gene (SMARCA2). We have examined the association of this polymorphism with schizophrenia in a family-based and case/control study. SMARCA2 was chosen as a candidate gene because of its specific role in developmental pathways, its high expression level in the brain and some evidence of its association with schizophrenia spectrum disorder from genome-wide linkage analysis. RESULTS: Family-based analysis with 281 complete and incomplete triads showed that there is no significant preferential transmission of any of the alleles to the affected offspring. Also, in the case/control analysis, similar allele and genotype distributions were observed between affected cases (n = 289) and unaffected controls (n = 273) in each of three Caucasian populations studied: French Canadian, Tunisian and other Caucasians of European origin. CONCLUSION: Results from our family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia

The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

<p>Abstract</p> <p>Background</p> <p>Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (<it>SLC6A4</it>) and the response of ADHD relevant behaviors with methylphenidate treatment.</p> <p>Methods</p> <p>Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the <it>SLC6A4 </it>gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.</p> <p>Results</p> <p>Mixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (<it>s+l_G= s'</it>) responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (<it>l_A</it>). No genotype main effects on either CGI-Parents or CGI-teachers were observed.</p> <p>Conclusions</p> <p>A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the <it>SLC6A4 </it>gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00483106</p

Relation between therapeutic response and side effects induced by methylphenidate as observed by parents and teachers of children with ADHD

<p>Abstract</p> <p>Background</p> <p>The desired (therapeutic) and undesired (side) effects of methylphenidate might have underlying correlations. The aim of this study was to explore the strength and the possible sources of these correlations.</p> <p>Methods</p> <p>One hundred and fifty-seven children with ADHD (6-12 years) were administered placebo and methylphenidate (0.5 mg/kg in a divided b.i.d. dose), each for a one-week period, in a double-blind, crossover trial. Therapeutic response was assessed using the Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers), while side effects were assessed using the Barkley Side Effects Rating Scale (SERS).</p> <p>Results</p> <p>The side effect profile as assessed by the SERS was similar to that of previous studies with insomnia, decreased appetite, and headaches showing significant treatment effects (p < 0.005). These "somatic/physical" side effects did not correlate with CGI-Parents or CGI-Teachers. However, the side effects of "irritability", "proneness to crying", and "anxiousness" showed significant relationships with CGI-Parents. These "mood/anxiety" side effects showed no significant correlations with the CGI-Teachers.</p> <p>Conclusion</p> <p>The greater "mood/anxiety" side effects on methylphenidate and placebo, the less the parents observe improvement of their children while treated with methylphenidate. This suggests that the correlations between "mood/anxiety" side effects and poor response to treatment may be driven by observer effects rather than biological commonalities between therapeutic and side effects of methylphenidate.</p

Rai1 frees mice from the repression of active wake behaviors by light.

Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka 'masking') mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output