Can epigenetics shine a light on the biological pathways underlying major mental disorders?

A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.

A systematic review on mediators between adversity and psychosis: potential targets for treatment.

Various psychological and biological pathways have been proposed as mediators between childhood adversity (CA) and psychosis. A systematic review of the evidence in this domain is needed. Our aim is to systematically review the evidence on psychological and biological mediators between CA and psychosis across the psychosis spectrum. This review followed PRISMA guidelines. Articles published between 1979 and July 2019 were identified through a literature search in OVID (PsychINFO, Medline and Embase) and Cochrane Libraries. The evidence by each analysis and each study is presented by group of mediator categories found. The percentage of total effect mediated was calculated. Forty-eight studies were included, 21 in clinical samples and 27 in the general population (GP) with a total of 82 352 subjects from GP and 3189 from clinical studies. The quality of studies was judged as 'fair'. Our results showed (i) solid evidence of mediation between CA and psychosis by negative cognitive schemas about the self, the world and others (NS); by dissociation and other post-traumatic stress disorder symptoms; and through an affective pathway in GP but not in subjects with disorder; (iii) lack of studies exploring biological mediators. We found evidence suggesting that various overlapping and not competing pathways involving post-traumatic and mood symptoms, as well as negative cognitions contribute partially to the link between CA and psychosis. Experiences of CA, along with relevant mediators should be routinely assessed in patients with psychosis. Evidence testing efficacy of interventions targeting such mediators through cognitive behavioural approaches and/or pharmacological means is needed in future.

Epigenetics: A missing link between early life stress and depression.

Research has suggested a relationship between early life stress, and depression in particular longer episodes of depression with treatment resistant outcomes. However, the underlying mechanisms for this association remain poorly understood. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders are polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. In addition, the importance of the environment and its interaction with genes has pointed to a fundamental role of epigenetic mechanisms in psychiatric disorders, such as methylation of deoxyribonucleic acid (DNA), alterations, histone actions and regulation of gene expression by non-coding ribonucleic acids (RNAs). This article provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology and could lead to the identification of new targets for clinical intervention.

Exploring the Interplay Between Adversity, Neurocognition, Social Cognition, and Functional Outcome in People With Psychosis: A Narrative Review.

History of adversity is associated with subsequent psychosis, and with a spectrum of cognitive alterations in individuals with psychosis. These cognitive features go from neurocognitive aspects as working memory and attention, to complex social cognitive processes as theory of mind and emotional perception. Difficulties in these domains impact patients' social and occupational functioning, which has been shown to be more impaired in those previously exposed to childhood trauma. However, the interplay between adversity, neurocognition, and functioning is yet poorly understood. This narrative review aims to explore the evidence on whether deficits in neurocognitive and social cognitive domains may act as possible putative mechanism linking adversity with functioning in people with psychosis. We show available evidence supporting the link between adversity and poorer functioning in psychosis, especially in chronic stages; and replicated evidence suggesting associations of social cognition and, to a lesser extent, neurocognition with impairment in functioning in patients; although there is still an important gap in the literature testing particularly deficits in social cognition as mediator of the link between adversity and functional decline in psychosis. Targeting interventions focusing on neurocognition and social cognition in individuals with adversity and psychosis seems important, given the severe deterioration of these patients in these domains, although more research is needed to test whether such treatments can specifically improve functioning in individuals with psychosis and adversity. Literature aiming to understand the determinants of functional outcome should consider the pervasive impact of childhood adversity, and its related effects on cognition.

Motor signs in Alzheimer's disease and vascular dementia: Detection through natural language processing, co-morbid features and relationship to adverse outcomes.

BACKGROUND: Motor signs in patients with dementia are associated with a higher risk of cognitive decline, institutionalisation, death and increased health care costs, but prevalences differ between studies. The aims of this study were to employ a natural language processing pipeline to detect motor signs in a patient cohort in routine care; to explore which other difficulties occur co-morbid to motor signs; and whether these, as a group and individually, predict adverse outcomes. METHODS: A cohort of 11,106 patients with dementia in Alzheimer's disease, vascular dementia or a combination was assembled from a large dementia care health records database in Southeast London. A natural language processing algorithm was devised in order to establish the presence of motor signs (bradykinesia, Parkinsonian gait, rigidity, tremor) recorded around the time of dementia diagnosis. We examined the co-morbidity profile of patients with these symptoms and used Cox regression models to analyse associations with survival and hospitalisation, adjusting for twenty-four potential confounders. RESULTS: Less than 10% of patients were recorded to display any motor sign, and tremor was most frequently detected. Presence of motor signs was associated with younger age at diagnosis, neuropsychiatric symptoms, poor physical health and higher prescribing of psychotropics. Rigidity was independently associated with a 23% increased mortality risk after adjustment for confounders (p = 0.014). A non-significant trend for a 15% higher risk of hospitalisation was detected in those with a recorded Parkinsonian gait (p = 0.094). CONCLUSIONS: With the exception of tremor, motor signs appear to be under-recorded in routine care. They are part of a complex clinical picture and often accompanied by neuropsychiatric and functional difficulties, and thereby associated with adverse outcomes. This underlines the need to establish structured examinations in routine clinical practice via easy-to-use tools.

Dementia in People from Ethnic Minority Backgrounds: Disability, Functioning, and Pharmacotherapy at the Time of Diagnosis.

OBJECTIVES: Increasingly, older populations in the United Kingdom and other well-resourced settings are ethnically diverse. Despite a concern that the prevalence of dementia is expected to rise, very little is known about the association of ethnicity and dementia among aging older adults. The current study aimed to compare ethnic group differences in symptom profile, functioning and pharmacotherapy at dementia diagnosis. DESIGN: Cross-sectional study of patient characteristics at the point of dementia diagnosis. SETTING AND PARTICIPANTS: In total, 12,154 patients aged 65 years or older diagnosed with dementia in Southeast London between 2007 and 2015. METHODS: Data were extracted from the Clinical Record Interactive Search system, which provides anonymized access to the electronic health records of a large mental healthcare provider in Southeast London. Patients from ethnic minority backgrounds were compared with white British individuals on mental and physical well-being, functional scales and medications prescribed at dementia diagnosis, as well as subtype of dementia documented anywhere in the record. RESULTS: Compared with white British patients, Black African and Black Caribbean patients were more likely to present with psychotic symptoms and were less likely to have an antidepressant prescribed; white Irish patients had higher rates of substance/alcohol use and depressive symptoms were more prevalent in South Asian patients; all ethnic minority groups had higher odds of polypharmacy; and vascular dementia diagnoses were more common in Black and Irish ethnic minority groups. CONCLUSIONS AND IMPLICATIONS: At dementia diagnosis, there are substantial differences in noncognitive mental health symptoms and pharmacotherapy across ethnic minority groups and compared with the white British majority population. Some of these differences might reflect access/treatment inequalities or implicit unconscious bias related to ethnicity, influencing both. They need to be taken into consideration to optimize pathways into care and personalize assessment and management.

Clinical Course, Neurobiology and Therapeutic Approaches to Treatment Resistant Schizophrenia. Toward an Integrated View.

Despite considerable psychotherapeutic advancement since the discovery of chlorpromazine, almost one third of patients with schizophrenia remain resistant to dopamine-blocking antipsychotics, and continue to be exposed to unwanted and often disabling side effects, but little if any clinical benefit. Even clozapine, the superior antipsychotic treatment, is ineffective in approximately half of these patients. Thus treatment resistant schizophrenia (TRS), continues to present a major therapeutic challenge to psychiatry. The main impediment to finding novel treatments is the lack of understanding of precise molecular mechanisms leading to TRS. Not only has the neurobiology been enigmatic for decades, but accurate and early detection of patients who are at risk of not responding to dopaminergic blockade remains elusive. Fortunately, recent work has started to unravel some of the neurobiological mechanisms underlying treatment resistance, providing long awaited answers, at least to some extent. Here we focus on the scientific advances in the field, from the clinical course of TRS to neurobiology and available treatment options. We specifically emphasize emerging evidence from TRS imaging and genetic literature that implicates dysregulation in several neurotransmitters, particularly dopamine and glutamate, and in addition genetic and neural alterations that concertedly may lead to the formation of TRS. Finally, we integrate available findings into a putative model of TRS, which may provide a platform for future studies in a bid to open the avenues for subsequent development of effective therapeutics.