A genetic model for multimorbidity in young adults.

PURPOSE: Multimorbidity is increasing in younger adults but is understudied in this population. We used 22q11.2 deletion syndrome (22q11.2DS) as a genetic model to investigate multimorbidity in young to middle-aged adults. METHODS: Using the Anatomical Therapeutic Chemical (ATC) Classification System and setting five or more concurrent prescription medications as a proxy for multimorbidity, we compared data on 264 adults with 22q11.2DS (median age 27.8, range 17.3-68.3 years) with that for a community-based Canadian general population sample (n = 25,287). We used logistic regression to examine possible predictors of multimorbidity in 22q11.2DS. RESULTS: Multimorbidity in 22q11.2DS in the 25-44 year age group (34.7%) was significantly more prevalent than in the general population, both for the same age group (2.9%, prevalence ratio [PR] = 11.9, 95% CI 8.4-17.1) and compared with those aged 45-64 years (16.4%, PR = 2.1, 95% CI 1.6-2.7). Neuropsychiatric and endocrinological medication classes predominated. Within 22q11.2DS, older age and psychotic illness, but not sex, major congenital heart disease, or intellectual disability, were significant predictors of multimorbidity. CONCLUSION: The results indicate that adults with 22q11.2DS have a significant burden of illness with levels of multimorbidity comparable with those of the general population several decades older. In younger adults with multimorbidity, certain disease patterns may help identify genetic disorders in "big data."

All-cause mortality and survival in adults with 22q11.2 deletion syndrome.

PURPOSE: Given limited data available on long-term outcomes in 22q11.2 deletion syndrome (22q11.2DS), we investigated mortality risk in adults with this microdeletion syndrome. METHODS: We studied 309 well-characterized adults (age ≥17 years) with 22q11.2DS and their 1014 unaffected parents and siblings, using a prospective case-control design. We used Cox proportional hazards regression modeling and Kaplan-Meier curves to investigate effects of the 22q11.2 deletion and its associated features on all-cause mortality and survival. RESULTS: The 22q11.2 deletion (hazard ratio [HR] 8.86, 95% CI 2.87-27.37) and major congenital heart disease (CHD; HR 5.03, 95% CI 2.27-11.17), but not intellectual disability or psychotic illness, were significant independent predictors of mortality for adults with 22q11.2DS compared with their siblings. Amongst those with 22q11.2DS, there were 31 deaths that occurred at a median age of 46.4 (range 18.1-68.6) years; a substantial minority had outlived both parents. Probability of survival to age 45 years was approximately 72% for those with major CHD, and 95% for those with no major CHD (p < 0.0001). CONCLUSION: For adults with 22q11.2DS, the 22q11.2 deletion and more severe forms of CHD both contribute to a lower life expectancy than family-based expectations. The results have implications for genetic counseling and anticipatory care.

The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age.

Disorganized attachment is an important early risk factor for socioemotional problems throughout childhood and into adulthood. Prevailing models of the etiology of disorganized attachment emphasize the role of highly dysfunctional parenting, to the exclusion of complex models examining the interplay of child and parental factors. Decades of research have established that extreme child birth weight may have long-term effects on developmental processes. These effects are typically negative, but this is not always the case. Recent studies have also identified the dopamine D4 receptor (DRD4) as a moderator of childrearing effects on the development of disorganized attachment. However, there are inconsistent findings concerning which variant of the polymorphism (seven-repeat long-form allele or non-seven-repeat short-form allele) is most likely to interact with caregiving in predicting disorganized versus organized attachment. In this study, we examined possible two- and three-way interactions and child DRD4 polymorphisms and birth weight and maternal caregiving at age 6 months in longitudinally predicting attachment disorganization at 36 months. Our sample is from the Maternal Adversity, Vulnerability and Neurodevelopment project, a sample of 650 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 was obtained with buccal swabs and categorized according to the presence of the putative allele seven repeat. Macroanalytic and microanalytic measures of maternal behavior were extracted from a videotaped session of 20 min of nonfeeding interaction followed by a 10-min divided attention maternal task at 6 months. Attachment was assessed at 36 months using the Strange Situation procedure, and categorized into disorganized attachment and others. The results indicated that a main effect for DRD4 and a two-way interaction of birth weight and 6-month maternal attention (frequency of maternal looking away behavior) and sensitivity predicted disorganized attachment in robust logistic regression models adjusted for social demographic covariates. Specifically, children in the midrange of birth weight were more likely to develop a disorganized attachment when exposed to less attentive maternal care. However, the association reversed with extreme birth weight (low and high). The DRD4 seven-repeat allele was associated with less disorganized attachment (protective), while non-seven-repeat children were more likely to be classified as disorganized attachment. The implications for understanding inconsistencies in the literature about which DRD4 genotype is the risk direction are also considered. Suggestions for intervention with families with infants at different levels of biological risk and caregiving risk are also discussed.

Exploration of GP perspectives on deprescribing antidepressants: a qualitative study.

OBJECTIVE: Our aim was to explore general practitioners' (GPs) perceptions and experiences of discontinuing antidepressants. STUDY DESIGN: A qualitative study using semistructured interviews was undertaken between July 2019 and March 2020. The interviews were transcribed and analysed using a thematic analysis framework. SETTING: GPs affiliated with a university education and research network for general practice in Ireland. PARTICIPANTS: A purposive sample of GPs (n=10). RESULTS: Five themes emerged: shared decision-making; personalised therapy; medication-tapering toolkit; health service factors and concerns around tapering. GPs described being less likely to engage in deprescribing for patients with long-term and/or recurrent depression, older patients and those with comorbidities due to fear of relapse. Access to evidence-based psychological therapies, guidelines, information on rates of relapse, patient leaflets on discontinuing antidepressants and reminder prompts on GP-prescribing software were suggested to optimise appropriate antidepressant discontinuation. There was some suggestion that patients may use antidepressants for longer when talk therapy is not available or taken up. CONCLUSIONS: GPs are largely confident in their role of managing mild-to-moderate depression and deprescribing antidepressants. This study provides an insight into factors that influence GPs' decisions to deprescribe antidepressants. More information on rates of relapse after discontinuation would be helpful to inform decision-making.

The dopamine D4 receptor gene, birth weight, maternal depression, maternal attention, and the prediction of disorganized attachment at 36 months of age: A prospective gene×environment analysis.

BACKGROUND: Efforts to understand the developmental pathways for disorganized attachment reflect the importance of disorganized attachment on the prediction of future psychopathology. The inconsistent findings on the prediction of disorganized attachment from the dopamine D4 receptor (DRD4) gene, birth weight, and maternal depression as well as the evidence supporting the contribution of early maternal care, suggest the importance of exploring a gene by environment model. METHODS: Our sample is from the Maternal Adversity, Vulnerability, and Neurodevelopment project; consisting of 655 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 genotype was obtained with buccal swabs and categorized according to the presence of the 7-repeat allele. Maternal depression was assessed with the Center for Epidemiologic Studies Depression Scale at the prenatal, 6-, 12-, and 24-month assessments. Maternal attention was measured at 6-months using a videotaped session of a 20-min non-feeding interaction. Attachment was assessed at 36-months using the Strange Situation Procedure. RESULTS: The presence of the DRD4 7-repeat allele was associated with less disorganized attachment, ß=-1.11, OR=0.33, p=0.0008. Maternal looking away frequency showed significant interactions with maternal depression at the prenatal assessment, ß=0.003, OR=1.003, p=0.023, and at 24 months, ß=0.004, OR=1.004, p=0.021, as at both time points, women suffering from depression and with frequent looking away behavior had an increased probability of disorganized attachment in their child, while those with less looking away behavior had a decreased probability of disorganized attachment in their child at 36 months. CONCLUSIONS: Our models support the contribution of biological and multiple environmental factors in the complex prediction of disorganized attachment at 36 months.

Preschool children without 7-repeat DRD4 gene more likely to develop disorganized attachment style.

BACKGROUND: The current paper aimed to explore the effects of birth weight and the 7-repeat allele in Exon III of the dopamine D4 receptor (DRD4) gene on the development of disorganized attachment, a potential endophenotype of depression. Infants born with low birth weight have been shown to be at higher risk for later neurological impairments, psychological disorders or behavioural problems. The DRD4 gene is critical for the cognitive and emotional processes that are sub-served by neural circuits in the prefrontal cortex. This paper examined the main effect of birth weight and DRD4 on the development of disorganized attachment. METHODS: Data was used from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project. The sample consisted of 251 mother-child dyads with complete data. Attachment style was assessed using the modified separation-reunion procedure. RESULTS: There was no main effect for birth weight on disorganized attachment, (b = -0.001, p = 0.998). There was, however, a main effect for the DRD4 7-repeat polymorphism on disorganized attachment (b = -1.120, p = 0.004). LIMITATIONS: Compared to studies of similar design, the sample size in this study was relatively small. Additionally, a significant number of subjects did not have complete data. CONCLUSIONS: Children without the DRD4 7-repeat allele were more likely to have disorganized attachment than children with the DRD4 7-repeat allele. This indicates that the 7-repeate allele of the DRD4 gene may actually serve as a protective factor against disorganized attachment.