Globally, psychiatric disorders, such as anxiety disorder, bipolar disorder, schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD) are becoming more prevalent. Although the exact pathological alterations are not yet clear, recent studies have demonstrated that widespread changes of very complex metabolic pathways may partially underlie the pathophysiology of many psychiatric diseases. Thus, more attention should be directed to metabolic-based therapeutic interventions in the treatment of psychiatric disorders. Emerging evidence from numerous studies suggests that administration of exogenous ketone supplements, such as ketone salts or ketone esters, generates rapid and sustained nutritional ketosis and metabolic changes, which may evoke potential therapeutic effects in cases of central nervous system (CNS) disorders, including psychiatric diseases. Therefore, the aim of this review is to summarize the current information on ketone supplementation as a potential therapeutic tool for psychiatric disorders. Ketone supplementation elevates blood levels of the ketone bodies: D-β-hydroxybutyrate (βHB), acetoacetate (AcAc), and acetone. These compounds, either directly or indirectly, beneficially affect the mitochondria, glycolysis, neurotransmitter levels, activity of free fatty acid receptor 3 (FFAR3), hydroxycarboxylic acid receptor 2 (HCAR2), and histone deacetylase, as well as functioning of NOD-like receptor pyrin domain 3 (NLRP3) inflammasome and mitochondrial uncoupling protein (UCP) expression. The result of downstream cellular and molecular changes is a reduction in the pathophysiology associated with various psychiatric disorders. We conclude that supplement-induced nutritional ketosis leads to metabolic changes and improvements, for example, in mitochondrial function and inflammatory processes, and suggest that development of specific adjunctive ketogenic protocols for psychiatric diseases should be actively pursued.

/pdf/therapeutic-potential-of-exogenous-ketone-supplement-induced-249d1fufro.pdf

Therapeutic Potential of Exogenous Ketone Supplement Induced Ketosis in the Treatment of Psychiatric Disorders: Review of Current Literature

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with only symptomatic care available. Genome-wide association (GWA) studies can provide a starting point in the search for novel drug targets and possibilities of drug repurposing. Here, we explored the druggable genome in ADHD by utilising GWA studies on ADHD and its co-morbid conditions. First, we explored whether the genes targeted by current ADHD drugs show association with the disorder and/or its co-morbidities. Second, we aimed to identify genes and pathways involved in the biological processes underlying ADHD that can be targeted by pharmacological agents. These ADHD-associated druggable genes and pathways were also examined in co-morbidities of ADHD, as commonalities in their aetiology and management may lead to novel pharmacological insights. Strikingly, none of the genes encoding targets of first-line pharmacotherapeutics for ADHD were significantly associated with the disorder, suggesting that FDA-approved ADHD drugs may act through different mechanisms than those underlying ADHD. In the examined druggable genome, three loci on chromosomes 1, 4 and 12 revealed significant association with ADHD and contained nine druggable genes, five of which encode established drug targets for malignancies, autoimmune and neurodevelopmental disorders. To conclude, we present a framework to assess the druggable genome in a disorder, exemplified by ADHD. We highlight signal transduction and cell adhesion as potential novel avenues for ADHD treatment. Our findings add to knowledge on known ADHD drugs and present the exploration of druggable genome associated with ADHD, which may offer interventions at the aetiological level of the disorder.

/pdf/druggable-genome-in-attention-deficit-hyperactivity-disorder-1ck7t5evq7.pdf

Druggable genome in attention deficit/hyperactivity disorder and its co-morbid conditions. New avenues for treatment.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented.

https://www.mdpi.com/2075-4426/11/3/166/pdf

ADHD: Reviewing the Causes and Evaluating Solutions.

Attention-deficit/hyperactivity disorder (ADHD) frequently co-occurs with intellectual disability in children, and may further compromise learning. Methylphenidate is a first-line treatment for ADHD, however no previous meta-analysis has evaluated its overall efficacy for ADHD in children with comorbid intellectual disability (ID) or borderline intellectual functioning. The PubMed/MEDLINE, Cochrane CENTRAL and ScienceDirect databases were systematically searched from inception through 2018/7/15 for clinical studies that investigated the effects of methylphenidate in children with ADHD and ID. A random-effects model meta-analysis was used for data synthesis. Eight studies (average Jadad score = 2.5) enrolling 242 participants receiving methylphenidate and 181 participants receiving placebo were included. The meta-analysis showed that methylphenidate led to a significant improvement in ADHD symptoms relative to placebo (Hedges’ g = 0.878, p < 0.001). Meta-regression analysis pointed to an association between the dose of methylphenidate and overall improvement in ADHD severity (slope = 1.334, p < 0.001). Finally, there was no significant difference in drop-out rate [odds ratio (OR) = 1.679, p = 0.260] or rate of treatment discontinuation due to adverse events (OR = 4.815, p = 0.053) between subjects receiving methylphenidate and those taking placebos. Our study suggests that methylphenidate retains its efficacy in children with ADHD and borderline intellectual functioning or ID.

/pdf/therapeutic-effects-of-methylphenidate-for-attention-deficit-3wl2i4iztz.pdf

Therapeutic effects of methylphenidate for attention-deficit/hyperactivity disorder in children with borderline intellectual functioning or intellectual disability: A systematic review and meta-analysis

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression.

Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children and adolescents. ADHD affects multiple aspects of an individual’s life and functioning in family, social, and academic realms. Effective management of ADHD is necessary for children and adolescents and may include non-pharmacologic treatments, pharmacologic therapy including use of stimulant and non-stimulant medications, or a combination of the different treatment modalities. In general, medications used to treat ADHD are safe and effective. Medical practitioners can follow a step-wise approach in the selection and adjustment of pharmacologic agents to treat ADHD, while working closely with families, caregivers, and other medical and educational professionals to form appropriate treatment plans. This article reviews practical aspects of pharmacological treatment of ADHD in children and adolescents.

Pharmacologic management of attention deficit hyperactivity disorder in children and adolescents: a review for practitioners

A Unique Case of Sudden Cardiac Death in an Infant.

A preterm infant with a ventricular septal defect and facial dysmorphisms.

### Prenatal and Birth Histories

### Presentation

After birth, the infant was admitted to the NICU because of prematurity. He required supplemental oxygen through a nasal cannula for a brief period (<1 week) and was successfully weaned to room air. Echocardiography revealed a large perimembranous ventricular septal defect (VSD) with 2 small ventricular muscular defects. The team identified facial dysmorphisms and ordered a microarray analysis.

### Physical Examination (After Birth)

Sharmeen Samuel

Papers

Pharmacologic management of attention deficit hyperactivity disorder in children and adolescents: a review for practitioners

A Unique Case of Sudden Cardiac Death in an Infant.

A Unique Case of Facial Dysmorphism in an Infant