Neurobiological mechanisms and therapeutic impact of electroconvulsive therapy (ECT).

Electroconvulsive therapy (ECT) is an efficient therapeutic resource for psycho-pharmacotherapeutic resistant forms of depression. ECT is a form of electrical brain stimulation involving the induction of a controlled seizure, clinically similar to an epileptic seizure, that is initiated in the prefrontal region of the brain and spreads to the cortex and subcortex, including the diencephalic structures. This is achieved by creating a transcranial electric field and synchronously depolarizing neuronal membranes. The mechanisms of action of ECT are not yet fully understood, but several hypotheses have been proposed to explain how it affects the brain: neurotransmitter changes, neuroplasticity, network connectivity, endocrine system regulation and changes in regional cerebral blood flow and regional metabolism.

Genetic polymorphism and neuroanatomical changes in schizophrenia.

The article is a review of the latest meta-analyses regarding the genetic spectrum in schizophrenia, discussing the risks given by the disrupted-in-schizophrenia 1 (DISC1), catechol-O-methyltransferase (COMT), monoamine oxidases-A∕B (MAO-A∕B), glutamic acid decarboxylase 67 (GAD67) and neuregulin 1 (NRG1) genes, and dysbindin-1 protein. The DISC1 polymorphism significantly increases the risk of schizophrenia, as well injuries from the prefrontal cortex that affect connectivity. NRG1 is one of the most important proteins involved. Its polymorphism is associated with the reduction of areas in the corpus callosum, right uncinate, inferior lateral fronto-occipital fascicle, right external capsule, fornix, right optic tract, gyrus. NRG1 and the ErbB4 receptor (tyrosine kinase receptor) are closely related to the N-methyl-D-aspartate receptor (NMDAR) (glutamate receptor). COMT is located on chromosome 22 and together with interleukin-10 (IL-10) have an anti-inflammatory and immunosuppressive function that influences the dopaminergic system. MAO gene methylation has been associated with mental disorders. MAO-A is a risk gene in the onset of schizophrenia, more precisely a certain type of single-nucleotide polymorphism (SNP), at the gene level, is associated with schizophrenia. In schizophrenia, we find deficits of the γ-aminobutyric acid (GABA)ergic neurotransmitter, the dysfunctions being found predominantly at the level of the substantia nigra. In schizophrenia, missing an allele at GAD67, caused by a SNP, has been correlated with decreases in parvalbumin (PV), somatostatin receptor (SSR), and GAD ribonucleic acid (RNA). Resulting in the inability to mature PV and SSR neurons, which has been associated with hyperactivity.

Morphological classification and changes in dementia (Review).

The progressive functional decline that involves both cognitive and neuropsychiatric symptoms characteristic to dementia is one of the leading research topics. The risk for dementia is an intertwined mix between aging, genetic risk factors, and environmental influences. APOEε4, which is one of the apolipoprotein E (APOE) alleles, is the major genetic risk factor for late-onset of the most common form of dementia, Alzheimer's. Advances in machine learning have led to the development of artificial intelligence (AI) algorithms to help diagnose dementia by magnetic resonance imaging (MRI) in order to detect it in the preclinical stage. The basis of the determinations starts from the morphometry of cerebral atrophies. The present review focused on MRI techniques which are a leading tool in identifying cortical atrophy, white matter dysfunctionalities, cerebral vessel quality (as a factor for cognitive impairment) and metabolic asymmetries. In addition, a brief overview of Alzheimer's disease was presented and recent neuroimaging in the field of dementia with an emphasis on structural MR imaging and more powerful methods such as diffusion tensor imaging, quantitative susceptibility mapping, and magnetic transfer imaging were explored in order to propose a simple systematic approach for the diagnosis and treatment of dementia.

Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review).

The aim of this overview was to outline the pathophysiology, common comorbidities and current therapeutic modalities in the treatment/management of restless legs syndrome (RLS) a sensorimotor neurological disorder. The main symptom in RLS is a compelling compulsion to move the legs and a sense of restlessness at rest most commonly occurring during the night and improving with movement. The prevalence of secondary RLS among comorbid conditions such as idiopathic pulmonary fibrosis, end-stage renal disease, irritable bowel syndrome and attention deficit/hyperactivity disorder have further elucidated our understanding of the role of the iron-dopamine hypothesis as an etiopathogenetic hallmark in RLS and the efficacy of therapeutic approaches in milder to more severe forms. Currently, RLS treatment uses only symptomatic agents, since a disease-modifying therapy does not yet exist. The phenomena of rebound and augmentation have become central phenomena in overcoming the pharmacotherapeutic challenges when treating with dopaminergic agents in RLS. Considering alternative nonpharmacological therapies, especially for the treatment of RLS in pregnancy has a significant role and positive clinical outcome for patients in controlling symptoms.

Neuroplasticity and depression: Rewiring the brain's networks through pharmacological therapy (Review).

In modern society, depression is one of the most common mental illness; however, its pathophysiology is not yet fully understood. A great body of evidence suggests that depression causes changes in neuroplasticity in specific regions of the brain which are correlated to symptom severity, negative emotional rumination as well as fear learning. Depression is correlated with atrophy of neurons in the cortical and limbic brain regions that control mood and emotion. Antidepressant therapy can exhibit effects on neuroplasticity and reverse the neuroanatomical changes found in depressed patients. The investigation of fast-acting agents that reverse behavioral and neuronal deficiencies of chronic depression, especially the glutamate receptor antagonist NMDA ketamine, and the cellular mechanisms underlying the rapid antidepressant actions of ketamine and related agents are of real interest in current research. Actual medication such as serotonin (5-HT) selective reuptake inhibitor (SSRI) antidepressants, require weeks to months of administration before a clear therapeutic response. The current review aimed to underline the negative effects of depression on neuroplasticity and present the current findings on the effects of antidepressant medication.

A multidisciplinary approach to the management of liver disease and alcohol disorders in psychiatric settings (Review).

Society is burdened with the uncontrolled use of alcohol, an ongoing issue, with a substantial associated morbidity and a pressing economical reverberation. It is inevitable that a series of psychiatric patients who display alcohol disorders will be admitted to hospital while also suffering from health conditions, such as liver disease, due to the consumption of alcohol. Managing comorbid patients in a psychiatric facility is a delicate matter that requires a collaborative team. The aim of this systematic paper is to highlight the following: The possibility of treating alcohol use disorder (AUD) and alcohol withdrawal syndrome (AWS) overlapping alcohol liver disease (ALD) within a psychiatric institution, and the importance of a collaborative multidisciplinary team; correctly dosing psychoactive medication when metabolism is affected by ALD; deciding when is it necessary to seek a transfer to a general hospital. Prescribing medication in patients suffering from ALD is still a not a fully documented territory. Protein binding, metabolism, bioavailability, extraction ratios, excretion route, and half-life must be taken into consideration as well as frequently repeating liver panels. Studies suggest that short-acting benzodiazepines are preferred over their alternatives when treating AWS in ALD. All anticonvulsants can be used in patients with decompensated liver disease with caution, although newer generation antiepileptic agents should be first line. Propofol is favored to benzodiazepines or opioids in the case of decompensated cirrhosis. Patients with ALD are likely to be further compromised by the potential hepatocytotoxicity of some pharmacological agents. On that account, having an integrated perspective of the medical case while taking into consideration the underlying illness as well as possible drug interaction is crucial in treating AUD or AWS in a psychiatric institution.

Efficacy of electroconvulsive therapy as a potential first-choice treatment in treatment-resistant depression (Review).

Electroconvulsive therapy (ECT) is a technique that has been used since 1938 to treat several psychiatric disorders as a replacement for chemically induced seizures. Despite its history of stigma, controversy and low accessibility, ECT is found to be beneficial and efficient in severe cases of depression where medication fails to bring results. Titration tables developed over time, based on evidenced-based medicine, have made this treatment technique safe and, in some cases, the first choice of treatment. The aim of the review was to summarize the research conducted on the efficacy of ECT on major depressive disorder and variables studied such as technique, comorbidities and medication as well as the effects and outcomes of this procedure. At the same time, the application and correlations with other psychiatric and neurological disorders, including catatonia, agitation and aggression in individuals with dementia, schizophrenia, and epilepsy were assessed. There are no statistically demonstrated effects due to the fact that a small number of moderate-quality studies have been published; however, the combination of ECT technique with standard medication and care, can improve patient outcome. Furthermore, with regard to ECT, widespread and robust volume changes in both cortical and subcortical regions have been shown. Antidepressant response and volumetric increases appear to be limited by the specific neuroplasticity threshold of each patient.

Korsakoff syndrome: An overlook (Review).

This review aimed to analyze the latest neurobiological findings regarding Korsakoff syndrome, since alcoholism is the most prevalent addiction worldwide. In addition, we analyzed the optimal treatment that can be administered in order to minimize the symptoms and improve the outcome of these patients. The disruption of memory circuits within the brain of alcoholic patients results in the amnestic syndrome known as Korsakoff syndrome. It is generally characterized by a chronic neuropsychiatric syndrome caused by vitamin B1 (thiamine) deficiency. Other categories of patients can develop Korsakoff syndrome without consuming alcohol such as AIDS patients, terminally ill cancer patients, or patients with chronic infections and malnutrition. Vitamin B1 is required in the Krebs cycle for production of adenosine triphosphate (ATP). It is also a cofactor in the production of acetylcholine and certain neurotransmitters. Alcohol consumption can decrease the intake, gastrointestinal absorption and cellular utilization of vitamin B1. Treatment of alcohol withdrawal along with high doses of vitamin B1 can improve the general outcome of patients. A small percentage of patients can recover from Wernicke's encephalopathy with no permanent brain damage. The onset of Korsakoff syndrome darkens the prognosis. Alcohol abstinence is an absolute recommendation and prevents the extension of neural damage.

Genetic aspects in schizophrenia. Receptoral theories. Metabolic theories.

Ties between schizophrenia (SCZ) and genetics are undeniably significant issue prone to be discussed in the nowadays psychology. Recent research on this domain focuses more on specific genes and heredity (specifically monozygotic pairs of twins) for diagnosing SCZ, than on environmental influences. SCZ is considered a multifactorial disease, thought to convert from a merger of risk and biological genes and environmental factors that could alter and reshape the trajectory of brain development. On this regard, this review sums up recent and innovative methods of distinguishing schizophrenic features from other mental illnesses in patients, based on chromosomal and genes changes. The term "reverse genetics" is no longer up to date, being replaced with "genome scanning" and "positional cloning". For many researchers, genome scanning is continuing the reverse of the sensible strategy for detecting various important biological disorders, which may start from the discovery of a protein or any other molecule involved in a biological process, being followed by its gene cloning. Genes being discovered in this manner could become candidate genes for the disease. However, genome scanning occurs through testing each chromosomal segment (or mitochondrial genome) for the counter transmission of the disease.

Aggressive behavior in psychiatric patients in relation to hormonal imbalance (Review).

Aggressive behavior is one of the main characteristics of different psychiatric disorders such as: personality disorders (antisocial personality disorder, borderline personality disorder), schizophrenia, intermittent explosive disorder, post-traumatic stress disorder, bipolar disorder, depression, alcohol/substance induced psychiatric disorders. Epidemiological evidence shows that always there is a higher risk of violence and aggressivity among patients with psychiatric disorders compared with general population. Researchers have tried many times to narrow the theories that can explain such a behavior, starting from models that involve a link between illness and aggression going up to external-environmental factors including the therapeutic relation in the hospital. Even if the majority of studies are centered on intoxications (with alcohol or other substances that potentiate the aggressive behavior) we will highlight another somatic dimension linked with this behavior. In the following review we summarize the hormonal imbalances that have been noted to accompany aggressive behavior in different psychiatric disorders. Several studies have been made starting even at the age of ten corelating hormone cortisol with increase aggression, but patients with psychiatric disorders have a higher sensitivity in linking hormonal imbalance with their behavior.

Affective disorders: A question of continuing treatment during pregnancy (Review).

Fetal development, especially in the first trimester, has proven to be heavily influenced by external factors, such as chemical intake of medication. Chronic psychiatric treatment might interfere with the anatomical and physiological wellbeing of the fetus, because psychotropic medication proceeds past the placenta, into the amniotic fluid, and can enter breast milk. Hence some of the medications prescribed for mood disorders should be reconsidered during pregnancy, without sub-optimally treating when it is needed. A literature review is presented which systematically collects modern data and synthesizes previous interdisciplinary research findings on the safety of psychiatric treatment for affective disorders during pregnancy (term-based) and lactation. Antidepressants and mood stabilizers, fundamental strategies in treating affective disorders, have been classified by the FDA as C respectively D drugs pertaining to their risk, with some exception. Most guidelines recommend pharmacologically treating moderate-severe depression, preferably with SSRIs. Evidence advocates that drugs should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus. However, guidelines the American College of Obstetricians and Gynecologists state that antidepressants are a preferred first course of treatment and does not take into account the severity of the depression. Among mood-stabilizers, lithium is considered to be the safest option for pregnant women. Anticonvulsants have a higher risk of teratogenicity compared with lithium, with lamotrigine being the safest one. All mood stabilizers should be recommended in the lowest effective doses. There is controversy regarding the safety of second-generation antipsychotics during pregnancy and further research is required. Several case reports and meta-reviews have been published in order to emphasize the safety of electroconvulsive therapy (ECT) during pregnancy, but practitioners still stigmatize this procedure. Evaluating the overall risk-benefit ratio should be assessed by the medical care provider, taking into consideration current findings.

Gaps or links between hormonal therapy and schizophrenia? (Review).

Schizophrenia is considered the most severe and debilitating psychiatric disorder. During the 80's, first reports on abnormalities of the schizophrenic brain which could be objectively observed on MRI, CT scans and other imagistic techniques were published. This showed that schizophrenia is a disorder that goes beyond the functional aspect of the symptomatology. The ties between psychiatry and endocrinology are easily observed, even empirically, by any mental health practitioner, and mirrored by endocrinology specialists. Disorders related to menstruation phase of the menstrual cycle have a code in DSM-V, people expect women 'to have mental disturbances' during puberty, pregnancy, menopause and other periods of life known to cause a hormonal storm. Leaving aside those simple and common beliefs, any mental health specialist can observe the differences between men and women when it comes to psychopathology, and the differences between male and female patients when it comes to a severe disorder such as schizophrenia. Males present more severe symptoms; their evolution is worse and they tend to have more medico-legal issues. On the contrary, the current available treatments for schizophrenia tend to have some side effects easily observed by endocrinologists: from gynecomastia to breast asymmetry in women, hyperprolactinemia, weight gain and other metabolic disorders, the clinic shows us regularly what the science has already told us; that the impact of hormones on the developing brain, starting in utero and going on through life may hold the key to finding better treatments for debilitating disorders such as schizophrenia. This mini-review is focused on the role of estrogen in the evolution of schizophrenia and on reporting trials that showed how hormonal therapy (used mainly for breast cancer and osteoporosis) can improve the outcome of patients with schizophrenia.

Genetics of schizophrenia (Review).

A comprehensive review of the body of genetic studies on schizophrenia seems even more daunting than the battle a psychiatrist wages daily in the office with her archenemy of a thousand faces. The following article reunites some genetic, epigenetic and environmental factors of schizophrenia from revered and vast studies in a chronological and progressive fashion. Twin studies set the basics of heritability and a particular study by Davis and Phelps considers the widely ignored influence of prenatal environment in the development of schizophrenia. Mostly ignited by linkage studies, candidate gene studies explore further by fine-mapping the hypothesized variants [mostly in the forms single nucleotide polymorphisms (SNPs) and less but with greater impact copy number variations (CNVs)] associated with the disease. Genome-wide association studies (GWAS) increase considerably the sample sizes and thus the validity of the results, while the next-generation sequencing (NGS) attain the highest yet unreplicated level of validity results.

Immunological and hormonal mechanisms in Alzheimer's disease.

Alzheimer's disease (AD) is a disorder which is today treated and approached at the crossroad of two medical specialties - psychiatry and neurology. The insidious onset which can often mimic depressive disorders or other type of psychiatric disorders, the behavioral changes, the paranoid thoughts usually send people to the psychiatrist, while the brain changes observed on magnetic resonance imaging (MRI) scans and other imaging techniques may indicate the need for neurological monitoring also. The complex symptomatology and progression of this dementia requires a multidisciplinary approach and recent studies focused on adding a third perspective: a metabolic one. The common findings regarding type 2 diabetes and AD made some researchers to informally name it "the third type diabetes". This mini review aims to highlight the mechanisms through which brain insulin resistance can lead to cognitive impairment and to make a short overview of the current findings which demonstrate why insulin may be a promising adjunctive treatment of Alzheimer's dementia, for certain patients.

Brain changes in depression.

The present review addresses major depressive disorder (MDD) and the implications of antidepressant treatment in the field of brain neuroplasticity, an effect initially considered adjacent but currently passed as central in the process of remission of MDD. Both in experimental animal studies and in human studies in subjects with mood disorders, neuroplasticity is considered the fundamental mechanism of neural defense against stress. Stress is the mediator between neurofunctional, neuroendocrine, neurobiological and neuroimmune disorders and depressive pathology of various intensities. Neurons have a high potential to adapt to the influences of internal and external factors. We are talking about neuroplasticity at different levels: structural neuroplasticity involving adult neurogenesis (such as plastic changes, dendritic reconstruction, when the morphology of the spine is affected); synaptic functional neuroplasticity and molecular and cellular mechanisms involved. These two major dimensions explain the pathophysiology of depression, as well as the convergence of the mechanisms involved in stress, major depressive decompensations, and the concept of neuroplasticity as the present target for new effective and potent antidepressant treatments.

Mild TBI in the elderly - risk factor for rapid cognitive impairment in Alzheimer's disease.

In recent decades, traumatic brain injury (TBI) has become one of the most important health problems worldwide and is a major cause of morbidity, mortality and economic losses. Mild traumatic brain injury (mTBI) is less considered, with clinical underestimation leading to an epidemiological underevaluation of its incidence. Many of the signs and symptoms induced by mTBI are difficult to highlight clinically, especially those related to cognitive, behavioral, or emotional impairment. The complexity of the biological mechanisms induced by mTBI in the elderly determines synchronous pathogenic actions in which the vascular, inflammatory and neurodegenerative elements are intertwined. It is difficult to highlight a major pathogenic factor, since they act simultaneously, multimodally, in a real pathogenic cascade. The identification of mTBI and cerebral vascular changes by neuroimaging techniques, transcranial Doppler (TCD) or biological markers, suggests a potential prophylactic intervention by using neuroprotective factors as early as possible. Proper prophylaxis measures with neurotrophic treatment, rebalancing the gamma-aminobutyric acid (GABA)∕glutamate balance and combating the chronic inflammatory process, can become important pharmacological therapeutic targets.

Clozapine: An Updated Overview of Pharmacogenetic Biomarkers, Risks, and Safety-Particularities in the Context of COVID-19.

BACKGROUND: clozapine (CLZ) use is precarious due to its neurological, cardiovascular, and hematological side effects; however, it is the gold standard in therapy-resistant schizophrenia (TRS) in adults and is underused. OBJECTIVE: to examine the most recent CLZ data on (a) side effects concerning (b) recent pharmacological mechanisms, (c) therapy benefits, and (d) the particularities of the COVID-19 pandemic. DATA SOURCES: a search was performed in two databases (PubMed and Web of Science) using the specific keywords "clozapine" and "schizophrenia", "side effects", "agranulocytosis", "TRS", or "bipolar affective disorder (BAF)" for the last ten years. STUDY ELIGIBILITY CRITERIA: clinical trials on adults with acute symptoms of schizophrenia or related disorders. RESULTS: we selected 37 studies, randomized controlled trials (RCTs), and clinical case series (CCS), centered on six main topics in the search area: (a) CLZ in schizophrenia, (b) CLZ in bipolar disorder, (c) side effects during the clozapine therapy, (d) CLZ in pregnancy, (e) CLZ in early-onset schizophrenia, and (f) CLZ therapy and COVID-19 infection. LIMITATIONS: we considered RCTs and CCS from two databases, limited to the search topics. Conclusions and implications of key findings: (a) clozapine doses should be personalized for each patient based on pharmacogenetics testing when available; the genetic vulnerability postulates predictors of adverse reactions' severity; patients with a lower genetic risk could have less frequent hematological monitoring; (b) a CLZ-associated risk of pulmonary embolism imposes prophylactic measures for venous thromboembolism; (c) convulsive episodes are not an indication for stopping treatment; the plasma concentration of clozapine is a better side effect predictor than the dosage; (d) COVID-19 infection may enhance clozapine toxicity, generating an increased risk of pneumonia. Therapy must be continued with the proper monitoring of the white blood count, and the clozapine dose decreased by half until three days after the fever breaks; psychiatrists and healthcare providers must act together.

Clinical, ultrasound and histopathological correlation of clinically N0 neck nodes in patients with cancers of the pharynx and larynx.

BACKGROUND: The presence of metastatic cervical adenopathy is essential for treatment planning and prognosis assessment. Treatment of patients with head and neck cancer with clinically negative cervical lymphadenopathy (N0) remains controversial. Neck palpation, as the method used in tumor, node, metastasis (TNM) staging, has limitations and can provide false negative results in some cases. Lymph node metastases are associated with a reduced survival rate but at the same time, neck dissection for the patient with N0 neck is not without risks or complications. OBJECTIVES: In prospective study, we compared palpation, ultrasonography (US) examination of the neck and histopathological examination in patients with cancers of the pharynx and larynx. PATIENTS, MATERIALS AND METHODS: Forty-six patients with cancers of the pharynx and larynx that presented with a N0 neck were prospectively analyzed. They were divided in two groups: 23 patients operated with an external approach including the control of the lymph node areas, and a second group of 23 patients operated using endoscopy and carbon dioxide (CO2) laser, no neck dissection - "watchful waiting policy". All patients have had a flexible endoscopy of the pharynx and larynx, US of the neck and all received surgical treatment for their primary tumor. Imaging was performed in selected cases. All the removed lymph nodes were sent for histopathology. US was also used as a follow-up method. The US features of the examined lymph nodes were: diameters [longitudinal (L) and transverse (T)]; the ratio of the two diameters (L∕T); shape; lymph node area; central hypodensity; regular∕irregular margins; aspect (homogeneous or not). RESULTS: US has detected 25 lymph nodes in the open surgery group and intraoperatively, we excised 31 (sensitivity of 80.6%). Ten lymph nodes showed metastases, with 100% accuracy of US, which have been confirmed both pathologically and immunohistochemically. US in the second group - patients treated with CO2 laser - detected at four patients 10 cervical lymph nodes that did not presented any malignant features. At recurrence alone, the US confirmed 100% presence of nodes metastases. CONCLUSIONS: US was superior to palpation and this method can be recommended as a diagnostic tool in preoperative assessment of patients without palpable metastasis (N0).