Outpatient Pharmacogenomic Screenings to Prevent Addiction, Overdose, and Suicide.

Point-of-care genetic testing for single nucleotide polymorphisms (SNPs) to improve psychiatric treatment in outpatient settings remains a challenge. The presence or absence of certain genomic alleles determines the activity of the encoded enzymes, which ultimately defines the individual's drug metabolism rate. Classification of poor metabolizers (PMs) and rapid/ultrarapid metabolizers (RMs/UMs) would facilitate personalization and precision of treatment. However, current pharmacogenomic (PGx) testing of multiple genes is comprehensive and requires quantitative analyses for interpretations. We recommend qualitative, fast-track, point-of-care screenings, which are one- or-two gene-based analyses, as a quick initial screening tool to potentially eliminate the need for an expensive quantitative send-out test, which is a costly and lengthy process. We speculate that these tests will be relevant in two major scenarios: 1) clinical psychiatry for treating disease states such as major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), where trial and error is still the mainstay of drug selection and symptom management, a process that is associated with significant delay in optimizing individualized treatment and dose, and thus response; and 2) pain management, where quickly determining an effective level of analgesia while avoiding a toxic level can cause a drastic improvement in mental health.

Major Depressive Disorder, Suicides, and the Role of Dimensional Psychiatry for Triaging in Primary Care Settings: A Case Series Retroanalysis.

Objective: The goal was to promote early diagnosis and referral of patients with depressive symptomology in the primary care setting using a biopsychosocial-informed risk stratification tool to prevent suicides. Methods: A qualitative analysis of military suicides stationed at Fort Eustis, Virginia, using demographics from Fatality Review Boards (FRBs) of 10 cases assessing shared biopsychosocial stressors was conducted. The case reviews were used to assess the failure modes and effects analyses (FMEA), prompting the development of a performance improvement (PI) plan via a risk stratification scale that recognizes opportunities for intervention in the primary care and supervisor/peer settings to improve patient outcomes. Results: FMEA revealed the presence and interplay of multiple biopsychosocial stressors specifically impacting relationships, occupational functioning, financial status, legal issues, and undiagnosed mental health conditions across the 10 suicides reviewed. Furthermore, the severity of each stressor was best examined from a dimensional perspective to gauge the impact on or impairment of the individual in the military setting. The dimensional use of biopsychosocial stressors is congruent with our hypothesis that an increase in duration and intensity of biopsychosocial stressors increases risk of suicide. Conclusion: This case series reveals a gap in suicide assessment and suggests the use of a dimensional approach to measure biopsychosocial stressors at the entry level, such as primary care settings, or in the case of the military, during routine counseling. Additionally, a risk stratification tool that crosses biopsychosocial domains could provide a more accurate assessment for self-harm, in turn enabling a timely referral to appropriate helping agencies, including nonclinical resources.

Blood-Brain Barrier: COVID-19, Pandemics, and Cytokine Norms.

Neuropsychiatric manifestations of COVID-19 have become increasingly common in published literature as the COVID-19 pandemic continues to devastate the world. Morbidity and mortality associated with COVID-19 infection is driving recognition of the need for potential research in prevention, effective treatment, and reducing fatalities. In this article, we highlighted discussions and proposals previously reported in our series of articles on the subject of the blood-brain barrier to prevent both neurological and psychiatric manifestations of viral infection. The time for a rapid translational approach to bring point-of-care diagnostics and early prevention/treatment tools to practice is now, and it deserves immediate attention.

Placental Barrier and Autism Spectrum Disorders: The Roles of Prolactin and Dopamine in the Developing Fetal Brain-Part II.

The inverse relationship between prolactin and dopamine is important in the context of treatment with antipsychotic medications in men and nonpregnant women with thought disorders. Likewise, increased levels of prolactin as confirmation of recent seizure and the reciprocal levels of prolactin and dopamine in both eclampsia (seizures) and pre-eclampsia might have significant potential effects on a growing fetus. In this article, we attempt to outline the influence of these associations on autism spectrum disorders (ASDs) in children born to mothers with established diagnoses of eclampsia and/or pre-eclampsia. Our previously published paper, "Placental Barrier and Autism Spectrum Disorders: The Role of Prolactin and Dopamine on the Developing Fetal Brain," summarized evidence for dysregulated dopamine and prolactin levels in the etiology of ASDs and suggested a possible method for assessing whether such aberrations increase the risk of ASDs. The present paper as Part 2 expands on the published data that support this theory and proposes a study design to corroborate this hypothesis.

Single Nucleotide Polymorphisms and the Central Nervous System: Potential Biomarkers in Identifying Suicide Risk.

The rate of completed suicides continues to rise across nations, cultures, socioeconomic classes, age groups, sexes, military personnel, veterans, and civilians from different backgrounds. Most concerning is the absence of diagnosed mental health disorders in the majority of these cases, per current literature reports. Efforts in the identification and possible prevention of this ultimate, tragic act of self-destruction have been minimally successful. In this article, the authors discuss the possible biological mechanisms including the role for potential markers, single nucleotide polymorphisms (SNPs), and their association with suicidal behaviors.

Placental Barrier and Autism Spectrum Disorders: The Role of Prolactin and Dopamine on the Developing Fetal Brain.

Dopamine and prolactin exhibit opposite effects on lactation. However, a possible role for increased prolactin/dopamine ratio in postpartum mood and thought disorders and as a prognostic indicator of the mother's future mental health has not been well investigated. Postpartum depression is a serious condition with potentially devastating outcomes for both the mother and the infant. Early detection and treatment of this condition can have impressive results. Treatment options include antidepressant medications for mood disorders and use of antipsychotics and electroconvulsive therapy to address postpartum psychosis. Although there are obvious benefits of such treatments on the welfare of the mother and her child, broader implications of these treatments on lactation and child growth and development are not known. This review article explores a possible link between in-utero exposure to a high maternal prolactin/dopamine ratio and subsequent development of autism spectrum disorders. We hypothesize that a comprehensive, biologically oriented approach to the use of psychotropics in the regulation of neurotransmission during pre- and postpartum periods may result in better outcomes in this population.

Insomnia and attention deficit hyperactivity disorder in pediatrics: a checklist for parents.

Attention deficit hyperactivity disorder is a commonly diagnosed condition in the pediatric as well as adult psychiatric population. Attention deficit hyperactivity disorder has undoubtedly been over diagnosed and treated with both stimulants and non-stimulants over the past few decades. Behavior problems in children are commonly noticed both by parents and teachers, leading to the formulation of attention deficit hyperactivity disorder diagnosis. Insomnia, on the other hand, is not as readily detected by parents and may result in behavioral problems at school. Several medical conditions responsible for causing insomnia may need to be ruled out before the diagnosis of attention deficit hyperactivity disorder is confirmed. In this article, we highlight symptoms common both to insomnia and attention deficit hyperactivity disorder by development of a checklist to help delineate the two conditions. The purpose of this checklist is to provide informational and educational tools both for parents and teachers to distinguish insomnia from attention deficit hyperactivity disorder. The ultimate goal of this paper is to improve diagnostic screening for attention deficit hyperactivity disorder by excluding conditions such as insomnia that may masquerade as attention deficit hyperactivity disorder.

GAD65 antibodies, chronic psychosis, and type 2 diabetes mellitus.

Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma aminobutyric acid, an inhibitory neurotransmitter. Autoantibodies to the glutamic acid decarboxylase 65 isoform have been associated with chronic psychotic disorders and are found in neurons and pancreatic islets. Blood samples were collected from normal controls (n=16), individuals with chronic psychosis with type 2 diabetes mellitus (n=3), and patients with chronic psychosis without diabetes (n=8). No differences were found between any of the groups for frequency of positive glutamic acid decarboxylase 65Ab samples (98th percentile of a healthy control group) or in mean values of glutamic acid decarboxylase 65Ab. Sample size was likely too small to detect differences if they do exist.

The blood brain barrier and the role of ratiometric molecular analysis in schizophrenia.

The etiology of schizophrenia and other chronic psychotic disorders is complicated considering the multifactorial contribution of developmental, biological, and environmental factors. The role of the blood brain barrier has not yet been established as part of schizophrenia etiology; however, in previous blood brain barrier articles, we discussed potential consequences of various biological abnormalities due to dysregulation of molecular components, such as cofactors,(1) signaling molecules,(2) enzymes,(3) cytokines,(4) and antibodies.(5) In this review, we will discuss the potential use of peripheral ratiometric molecular analysis relevant to the central nervous system for the evaluation of the development of schizophrenia.

Role of cholinergic system and calcium synchronization in schizophrenia.

A considerable body of evidence exists in the literature regarding impairment of signal-to-noise ratio in schizophrenia. The pathophysiologic role of cholinergic systems via calcium release and acetylcholine's involvement precedes dopamine regulation in processing information. We therefore hypothesize that acetylcholine dysregulation precedes dopamine dysregulation in schizophrenia. This is an earlier step associated with reception of the initial signal prior to the processing of a received signal by dopamine in the prefrontal cortex. The cholinergic system has a major impact on cognitive abilities, especially learning and memory, through acetylcholine. Reception and relay of sensory information through the process of arousal along the corticothalamic tracts to accomplish higher-level decision-making functions via acetylcholine is well established. The uncoupling of the received information (the signal) from the transfer of that information (the relay) to higher attentional and executive functions for processing of that information (the assembly) may possibly lead to altered perception.

The blood brain barrier and the role of cytokines in neuropsychiatry.

Cytokines have emerged in the past two decades as some of the most extensively studied peptide molecules contributing to the pathophysiology of many diseases. As a result of these translational efforts, discovery of drugs aimed at reducing damage caused by cytokines has been accomplished for some conditions. The characterization of the role of cytokines in the pathophysiology of neuropsychiatric disorders is still in its infancy. This article highlights the growing correlation of brain cytokine levels with corresponding psychiatric symptoms, known as cytokine-induced sickness behavior, comprising increased sleep, decreased appetite, decreased sexual drive, and overwhelming fatigue frequently combined with fever.

Thermoregulation and the role of calcium signalling in neurotransmission.

Understanding the functional capacity of the human brain at a molecular level continues to be a challenge despite modern scientific and technological advances. Extreme variations in thermoregulation, whether induced by genetic predisposition or changes in internal, external or central factors, appear to be caused by altered calcium signalling at the neurotransmitter level and are likely due to a compromised blood brain barrier (BBB) in the hypothalamic region. The objective of this hypothesis is to explore the complicated interactions between neurotransmission, calcium signalling, and thermoregulation resulting from a challenged BBB in the hypothalamic region of the brain.

Obstructive sleep apnea, hypoxia, and metabolic syndrome in psychiatric and nonpsychiatric settings.

Obesity continues to be a serious cause of morbidity and mortality globally and particularly in North America. Primary manifestations of obesity include obstructive sleep apnea (OSA) and depression associated with a decrease in immune defense mechanisms, possibly related to increased cytokine levels. Secondary manisfestations of obesity possibly result from a cascade of events and include insulin resistance/ hyperglycemia, hyperlipidemia, and hypertension-all of which comprise metabolic syndrome. This paper reviews sleep disturbances in general and OSA in psychiatric patients, particularly those who are obese.

Blood brain barrier: the role of pyridoxine.

The central nervous system (CNS) is a closed system guarded by the blood brain barrier (BBB), with a complicated network of microvascular endothelial cells, astrocytes, and neurons engaged in selective neurophysiological mechanisms. Exploration for a molecule such as a cofactor, hormone, enzyme, signaling molecule, or second messenger (collectively addressed as CHESS as we proceed), which has the ability to cross the BBB will be the goal of this hypothesis. The ratio of amino acids (AA) to neurotransmitters (NT) is over one-to-one thousand in the CNS, with the ultimate effect at the end receptor level. Diagnostic modalities utilizing oxygen and glucose for identifying organic brain diseases via functional properties have become popular. Delineation from the background signal, however, poses an enormous challenge. Targeting neurotransmitter metabolism with little or possibly no background signal using a cofactor able to cross the BBB is hypothesized.

Blood brain barrier: the role of calcium homeostasis.

Calcium as a molecule plays a significant role in the body, especially in the central nervous system. In its free form, it has been classified as a cofactor, second messenger, and signaling molecule, and, when bound, forms a protein and coenzyme. This is secondary to the critical, and at times, very sensitive reactions associated with it. Calcium homeostasis, especially in the context of the central nervous system, may have crucial implications in many neuropsychiatric conditions. The hypothesis presented will explore the link between the blood-brain barrier (BBB) and calcium homeostasis (CH) as it is a complex, physiological process. Absence of organic deficits associated with conditions, such as pervasive developmental disorder (PDD), autism spectrum disorders (ASD), mental retardation (MR), and attention deficit hyperactivity disorder (ADHD), in addition to other chronic psychiatric disorders, builds a more compelling case to explore CH in context of the BBB.

Blood Brain Barrier: The Role of GAD Antibodies in Psychiatry.

OBJECTIVE: Goal of our case control study was to establish the presence of antibodies to glutamic acid decarboxylase (GAD) in patients with chronic psychotic disorders. METHODS: Serum levels of GAD antibodies in 12 patients with chronic psychotic disorders (schizophrenia and schizoaffective disorders) and 10 age-matched healthy control subjects were evaluated utilizing enzyme linked immunosorbitent assay (ELISA). RESULTS: Antibodies to GAD in patients with chronic psychotic disorders have a higher mean than nonpatient control individuals. CONCLUSION: Our findings provide the first in-vivo evidence of positive GAD antibodies in chronic psychotic disorders and potentially may be used as a screening for these disorders.