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Ketamine is a NMDA receptor antagonist that has a rapid acting antidepressant effect with high efficacy in treatment-resistant patients. Ketamine is a beneficial antidepressant for many individuals with depression, but not all of the patients respond, and some even exhibit symptom deterioration. The discovery of repeatable and mechanistically relevant biomarkers would address a major gap in treatment response prediction. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted an umbrella review to evaluate the biomarkers of ketamine's antidepressant effect in individuals with depression. PubMed and copus were searched using terms appropriate to each area of research, from their inception until July 2022. Five systematic reviews and meta analyses including 108 studies with 4912 participants were included. Blood-based and neuroimaging biomarkers were investigated. The results of this review indicate that ketamine can produce an anti-inflammatory effect and decrease at least one inflammatory marker following administration. Data from neuroimaging studies demonstrated that the cingulate cortex is the key locus of ketamine's action. The majority of the blood-based, neuroimaging, and neurophysiological investigations reviewed herein indicate ketamine induced normalization of major depressive disorder pathogenesis via synaptic plasticity and functional connectivity. Currently, no biomarker/biosignature is sufficiently validated for clinical utility, but several are promising. Now that ketamine is more widely available, biomarker discovery and replication should be attempted in larger, real-world populations.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive inborn error of creatine synthesis that results in intellectual disability, epilepsy, expressive language delay, and dystonia. We report data from two siblings with an uncommon GAMT deficiency phenotype and their clinical, biochemical, imaging, and treatment findings. The older sibling had intellectual disability, epilepsy, and generalized dystonia. The younger sibling had intellectual disability and generalized dystonia. After treatment with creatine, verbal fluency improved, as well as dystonia and aggression. This study confirms that in patients with unexplained intellectual disability, epilepsy, and/or movement disorders, GAMT deficiency should be considered. GAMT-associated cerebral creatine deficiency syndrome is a potentially treatable condition and can be identified by elevated levels of guanidinoacetate in plasma or urine or by a significantly decreased creatine peak on magnetic resonance spectroscopy.

Few studies have evaluated the efficacy of ketamine-assisted psychotherapy (KAP) in the treatment of treatment-resistant depression (TRD) and substance use disorders (SUD).A systematic review of clinical trials reporting on the efficacy of KAP and discussing mechanisms of action, identified on PubMed and PsycInfo.Five randomized-controlled trials reported on the efficacy of KAP treatment and discussed active mechanisms. Four of the studies treated adults with SUD and a single study treated adults with TRD. Overall, KAP had a significant positive effect on primary outcome measures compared to controls, however, the data is mixed. The study examining KAP for TRD found no benefit.Lack of large, replicated clinical trials. No studies actively examining mechanisms of action.Evidence suggests that temporary neural changes caused by ketamine such as n-methyl-d-aspartate receptor (NMDAR) inhibition and increase of synaptic neuroplasticity affect treatment outcomes of KAP. Based on reports of preliminary findings, we speculate that adjunct psychotherapy, changes in perspective, and spirituality may also play a role.

Ketamine is a promising therapeutic option in treatment-resistant depression (TRD). The acute efficacy of ketamine in TRD has been demonstrated in replicated randomised-controlled trials (RCTs), but the generalizability of RCT data to real-world practice is limited. To this end, we conducted a systematic review (Search date: 25/12/2021; 1482 records identified) and meta-analysis of studies evaluating the real-world clinical effectiveness of ketamine in TRD patients. Four overlapping syntheses (Total n = 2665 patients; k = 79 studies) and 32 meta-regressions (Total n = 2050; k = 37) were conducted. All results suggest that the mean antidepressant effect is substantial (mean ± 95% CI, % responded = 45 ± 10%; p0.0001, % remitted = 30 ± 5.9%; p0.0001, Hedges g of symptomatological improvement = 1.44 ± 0.609; p 0.0001), but the effect varies considerably among patients. The more treatment-resistant cases were found to remit less often (p 0.01), but no such effect on response was evident (p 0.05). Meta-regressions also confirmed that the therapeutic effect does not significantly decline with repeated treatments (p 0.05). These results demonstrate that even the most treatment-resistant patients may benefit from ketamine, and that mid-to-long term treatment is effective in many patients.

Traumatic brain injury (TBI) is a major cause of death and disability. TBI can result in neuropsychiatric and cognitive problems as well as neurodegenerative pathologies that can appear right after or develop and persist years after injury.We conducted a double-blind, randomized, placebo-controlled clinical trial on patients who suffered from TBI three months to three years ago. The patients were randomized to placebo (n = 34) or K-Vie™ group (n = 46) for a treatment period of 3 months. The main primary outcomes include cognitive assessment in the Rey Auditory Verbal Learning Test-Recognition Test (RAVLT), Wechsler adult intelligence Digit Symbol Substitution Test (DSST) and trail-making test part B (TMT-B). Assessments were performed at baseline and at the month 3 follow-up visit. Linear mixed models were carried out to evaluate cognitive changes from baseline across all cognitive assessment tests.The current study showed significant (p 0.05) improvement in cognitive function of patients who were given K-Vie™ compared with placebo across the RAVLT, DSST and TMT-B performance assessments. A larger cohort would be beneficial to further confirm the clinical utility of K-Vie™ and assess its effects in acute phases of TBI.

Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic-inflammatory disease associated with poor outcomes and decreased quality of life. NAFLD is overrepresented in patients with psychiatric disorders like depression, bipolar disorder, and schizophrenia; however, a comprehensive review on NAFLD and psychiatric disorders remains to be delineated. This review endeavors to investigate the association of NAFLD with psychiatric disorders, including shared pathogenesis and future clinical derivatives. Extant literature suggests that patients with psychiatric disorders (in particular, mood disorders) are more susceptible to the development of NAFLD due to multiple reasons, including but not limited to hypothalamic–pituitary–adrenal axis dysregulation, metabolic syndrome, and chronic perceived stress. Moreover, the clinical manifestations of mood disorders (e.g., anhedonia, psychomotor retardation, lifestyle modification, etc.), and potentially long-term treatment with weight-gaining agents, differentially affect these patients, making them more prone to NAFLD. Considering the increased morbidity associated with both mood disorders and NAFLD, our review recommends regular screenings for NAFLD in select patients with mood disorders exhibiting signs of increased risk (i.e., obesity, metabolic syndrome, diabetes, or family history of NAFLD) for better diagnosis and holistic care of both potentially interrelated conditions.

Background Regardless of the cause of the superficial siderosis (SS) disease, which is bleeding, the source of bleeding cannot be found in some cases. Case presentation In this article, we report two cases with idiopathic SS. Case 1 presented with bilateral hearing loss, cognitive impairment, sleep disturbances, and tremors. Case 2 presented with sensory neural hearing loss, ataxia, and spastic paraparesis. In both cases, brain MRI indicated evidence of SS. CT myelogram and SPECT with labeled RBC couldn’t help finding the source of occult bleeding. Conclusion SS is a rare central nervous system disease caused by the deposition of hemosiderin in the brain and spinal cord, which results in the progression of neurological deficits. The cause of this hemorrhage is often subarachnoid haemorrhage, intracranial surgery, carcinoma, arteriovenous malformation, nerve root avulsion, and dural abnormality. The condition progresses slowly and, by the time diagnosis is confirmed, the damage is often irreversible. In our cases, brain MRI clarified the definitive diagnosis, but we could not find the source of bleeding. SS should be considered in cases with ataxia and hearing loss, even if no source of bleeding is found.

Objective. In this study, we aimed to evaluate the executive profile of juvenile myoclonic epilepsy (JME) patients using the Frontal Assessment Battery (FAB) as a bedside screening tool and investigate its association with seizure proximity, family history of epilepsy, and polytherapy/monotherapy with antiepileptic drugs (AEDs). Background. JME patients have deficits in various aspects of executive functions. FAB has proved to be a useful tool for evaluating executive functions in clinical settings. Methods. Thirty-one JME patients and 110 healthy controls (HCs) were enrolled in this study. The participants were assessed using six subsets of FAB, including conceptualization, mental flexibility, motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. Results. Compared to HCs, JME patients showed lower scores in conceptualization, mental flexibility, programming, sensitivity to interference, and total FAB. The number of AEDs (polytherapy versus monotherapy) and duration of time since the last seizure had no significant effect on FAB scores in JME patients. We found significant associations between disease duration and conceptualization, mental flexibility, inhibitory control, and total FAB score only in JME patients with recent seizure. Finally, receiver operating characteristic (ROC) analysis showed area under the curve (AUC) of 0.971 (95% confidence interval (CI): 0.947–0.994) for FAB total score, 0.933 for conceptualization (95% CI: 0.973-894), and 0.836 for mental flexibility (95% CI: 0.921-751). Conclusions. In summary, JME patients had deficits in different aspects of executive functions. FAB is a useful clinical tool for evaluation of executive functions in JME patients.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by a progressive decline of cognitive performance, which has a harmful impact on social activities. AD is the main cause of dementia and loss of functional independence in the elderly. AD is a worldwide concern because of its adverse consequences and expanding prevalence and incidence. Vitamin D is the most common nutritional deficiency worldwide among children and adults. In addition to its classical function of bone metabolism regulation, vitamin D exhibits multiple biological targets mediated by the vitamin D receptor (VDR). Vitamin D is a risk factor for a wide range of diseases and, as a neurosteroid, has an essential role in nervous system development and protection. Vitamin D regulates mechanisms involved in the pathogenesis of AD, including phagocytosis of amyloid-beta plaques, anti-inflammatory action, antioxidant action, regulation of intraneuronal calcium, ischemic zone size reduction, regulation of choline acetyltransferase enzyme and neurotrophic agents. This study aimed to evaluate the association between AD and vitamin D deficiency. Methods: In this case-control study, 44 Alzheimer’s disease patients (diagnosed based on DSM-IV-TR criteria) compared with 40 patients that had no disease related to vitamin D. This study was performed in the neurology clinics of Roozbeh and Imam Khomeini Hospitals in Tehran, from April to March 2015. The demographic data were collected. After obtaining informed consent, venous blood was taken by clinical staff to measure the level of 25-hydroxyvitamin D3. Statistical analysis was performed on data. Results: The Mean age was 71.55 years old (69.88 for females and 73.74 for males) in the case group. Mean vitamin D levels were 26.31 ng/ml and 36.41 ng/ml in case and control groups, respectively. Vitamin D level was deficient (< 30 ng/ml) in 75% of patients, of which 23% were severely deficient (< 10 ng/ml). Statistical analysis showed no significant relationship between Alzheimer's disease and vitamin D levels (P=0.057), but when participants categorized into three groups based on serum vitamin D levels (deficient, insufficient, sufficient), we found a significant relationship between them (P=0.019). Conclusion: Our results confirm the association between vitamin D deficiency and Alzheimer's disease. Vitamin D supplementation should be considered in individuals at risk of Alzheimer's disease to reach sufficient vitamin D level.

Multiple lines of evidence have implicated brain-derived neurotrophic factor (BDNF) in treatment-resistant depression (TRD). The aim of this synthesis was to determine the impact of TRD treatments on peripheral BDNF levels, and ascertain whether these changes are associated with antidepressant effects. Thirty-six articles involving 1198 patients with TRD were included herein. Electroconvulsive therapy (ECT), ketamine, and repetitive transcranial magnetic stimulation (rTMS) were the most common TRD treatments investigated. Serum BDNF levels significantly increased in six, two, four and one studies following ECT, ketamine, rTMS and atypical antipsychotics, respectively. The estimated mean baseline serum BDNF concentration in TRD patients ± 95% CI was 15.5 ± 4.34 ng/mL. Peripheral BDNF levels significantly increased overall (Hedges' g ± 95% CI = 0.336 ± 0.302; p0.05), but no association with depressive symptoms was found (p ≥ 0.05). These results demonstrate that peripheral measurements of total BDNF (i.e., mature and percursor forms of BDNF) are inadequate predictors of treatment response in TRD patients, and other considerations suggest that this would still apply to separable measurements of mature BDNF and its precursor.

Ketamine has demonstrated rapid and significant antidepressant effects in patients with treatment resistant depression (TRD). Herein, we conducted a systematic review to determine ketamine's efficacy as a function of the stage of treatment resistance (e.g., number of failed treatments) among individuals with TRD.A systematic search of PubMed and Scopus from inception to August 2021 was conducted. Where applicable, the studies were categorized into low and high stages of resistance, where low category included studies where the mean number of failed antidepressants was3 or had a higher proportion of subjects with ≤2 antidepressant trials. Reported indicators of treatment resistance and efficacy were extracted from randomized-controlled trials (RCTs) assessing ketamine or esketamine for TRD.In total, 18 RCTs were included in the current review. There was variability across reported indicators of disease severity, definition of treatment resistance, as well as treatment protocols, preventing clear direct and indirect comparison of relative efficacy of ketamine at different stages of treatment resistance. Ketamine was effective in reducing depressive symptoms in RCTs at both lower and higher stages of treatment resistance; however, the effect size and duration of effects was greater in RCTs of lower stage of treatment resistance.Our findings suggested that ketamine has antidepressant efficacy across all identified stages of treatment resistance, however with increasing failed treatment trials, treatment might be less efficacious. At this time, the comparative efficacy as a function of resistance stage remains to be well-established. Evaluation of participant level data is required to more clearly determine the association between level of treatment resistance and likelihood of response.

Background: Ketamine is an emerging treatment for treatment-resistant depression (TRD) associated with rapid and robust improvements in depressive symptoms and suicidality. However, the efficacy and safety of ketamine in transitional age youth (TAY; age 18–25) populations remains understudied. Methods: In this retrospective analysis, TAY patients ( n = 52) receiving ketamine for TRD were matched for sex, primary diagnosis, baseline depression severity, and treatment resistance with a general adult (GA) sample (age 30–60). Patients received four ketamine infusions over 2 weeks (0.5–0.75 mg/kg over 40 min). The primary outcome was the change in Quick Inventory of Depressive Symptomatology Self-Report 16-item (QIDS-SR16) over time. Secondary outcomes were changes in QIDS-SR16 suicidal ideation (SI) item, anxiety (Generalized Anxiety Disorder 7-item (GAD-7)), and adverse effects (ClinicalTrials.gov: NCT04209296). Results: A significant main effect of infusions on reduction of total QIDS-SR16 ( p Conclusion: Ketamine was associated with comparable clinical benefits, safety, and tolerability in a TAY sample as compared to a matched GA TRD sample.

Psychiatric and metabolic disorders are highly comorbid and the relationship between these disorders is bidirectional. The mechanisms underlying the association between psychiatric and metabolic disorders are presently unclear, which warrants investigation into the dynamics of the interplay between metabolism, substrate utilization, and energy expenditure in psychiatric populations, and how these constructs compare to those in healthy controls. Indirect calorimetry (IC) methods are a reliable, minimally invasive means for assessing metabolic rate and substrate utilization in humans. This review synthesizes the extant literature on the use of IC on resting metabolism in psychiatric populations to investigate the interaction between psychiatric and metabolic functioning. Consistently, resting energy expenditures and/or substrate utilization values were significantly different between psychiatric and healthy populations in the studies contained in this review. Furthermore, resting energy expenditure values were systematically overestimated when derived from predictive equations, compared to when measured by IC, in psychiatric populations. High heterogeneity between study populations (e.g., differing diagnoses and drug regimens) and methodologies (e.g., differing posture, time of day, and fasting status at measurement) impeded the synthesis of results. Standardized IC protocols would benefit this line of research by enabling meta-analyses, revealing trends within and between different psychiatric disorders.

Over the past two decades, ketamine has emerged as a novel effective and rapid-acting antidepressant. While the vast majority of studies on ketamine have focused on its ability to reduce the severity of depression broadly, its effectiveness in specific domains such as cognition, anhedonia, suicidality, and workplace/social/scholastic functionality has been neglected. Similarly, current treatments (e.g., SSRIs and SNRIs) aim to improve overall depression severity, which often results in the persistence of one or more residual symptom domains and prevents full recovery to premorbid functionality. In this review, we narratively synthesize the literature pertaining to the effectiveness of ketamine in treating key domains of depressive symptomatology (i.e., cognition, anhedonia, suicidality, and psychosocial functionality). Our findings suggest that ketamine is effective across domains varyingly, with the strongest evidence being for its ability to reduce suicidality. The rapid acting nature of ketamine further supports its use in treating suicidality and potentially preventing the completion of suicide. Evidence for the effectiveness of ketamine in other domains is weak, primarily due to a lack of robust studies specifically designed to assess these domains as primary outcomes. Future studies should scrutinize the effects of ketamine on specific domains of depression to optimize its implementation.

Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of deficits in cognitive functions which has significant implications for quality of life. Psychostimulants are demonstrated to improve symptoms of inattention and hyperactivity/impulsivity, however, their impact on cognition remains incompletely characterized. Herein, the aim of this systematic review is to synthesize the extant literature reporting on the effects of psychostimulants on cognitive function in individuals with ADHD.A systematic search of PubMed, Scopus, and Web of Science from inception to July 2021 was conducted. Additional studies were identified through Google Scholar and a manual search of the reference lists of relevant articles. Inclusion criteria were original studies that evaluated the cognitive function of individuals with ADHD taking psychostimulants drugs. We assessed the quality of the included papers using the Newcastle-Ottawa scale (NOS).A total of 10 studies involving 753 subjects with ADHD and 194 healthy controls were identified and eligible for inclusion. Nine studies evaluated the impact of methylphenidate on cognitive function and one study investigated the use of lisdexamfetamine. Results indicated that attentional deficits such as memory, vigilance, divided attention, phasic and tonic alertness, and focused attention were improved in ADHD patients treated with psychostimulants. The efficacy of psychostimulants in improving other domains of cognition remains inconclusive due to conflicting evidence or insignificant findings (ie. academic performance and executive function). Overall, results indicate that psychostimulants may improve only select domains of cognition (ie. memory and attention).Psychostimulants are reported to improve several disparate aspects of cognition among individuals with ADHD. Further research is needed to better understand the complex relationships between cognition and behavior in ADHD, as well as the impact of medication on these distinct aspects of functioning. Further research is also needed to determine whether the pro-cognitive effect of stimulants would be transferable to other mental disorders.

Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning.

Replicated clinical trials have demonstrated rapid and robust antidepressant effects with ketamine in treatment resistant mood disorders. Sex (biological) and gender differences in therapeutic effects for any new intervention is an important consideration, however, the differential efficacy, safety and tolerability of ketamine in males versus females remains underexplored. The objective of the present systematic review is to identify and qualitatively synthesize all published clinical studies relevant to the sex differential effects of ketamine for mood disorders. A systematic search of PubMed, Medline, and PsycInfo from inception until January 20, 2021, yielded 27 reports including 1715 patients (742 males and 973 females) that met inclusion criteria. Results from the vast majority of studies (88.8%) do not support significant sex differences in antidepressant response, tolerability or safety of ketamine. Nine (33.3%) of the reports included a bioanalytical component in the analysis and only one reported on sex differences. Evidence from the present review does not support clinically or statistically significant sex differences in therapeutic effects with ketamine. Nevertheless, future studies should continue to consider sex and biological sex differences in study design and data analytic plans.

This cross-sectional study is aimed at assessing the effects of opium use disorder (OUD) on attention, working memory, and information-processing speed. Thirty outpatients with OUD and 20 healthy controls (HCs) were assessed using a neuropsychological battery consisted of Auditory Verbal Learning Test-Revised (AVLT-R), Brief Visuospatial Memory Test-Revised (BVMT-R), Digit Forward and Backward Tests (DFT and DBT), and WAIS-R Digit Symbol Substitution Test (DSST). The most affected cognitive functions in patients with OUD were detected by DBT and DSST. However, we found no significant difference between patients according to the route of administration. Within patients with OUD, DBT score was associated with opium use quantity (OUQ) ( r = − 0.385 ), and DBT ( r = 0.483 ) and DSST ( r = 0.542 ) scores were correlated with duration of use. Our findings indicated that working memory and information-processing speed are the most affected domains of cognitive functioning. DBT and DSST could be used as brief assessments in clinical settings to screen for cognitive deficits in patients with OUD.

Psychedelics are a hallucinogenic class of psychoactive drugs with the primary effect of activating non-ordinary states of consciousness. Due to the positive preliminary findings of these drugs in the treatment of psychiatric disorders, the number of registered clinical studies has risen significantly. In this paper, clinical studies registered on clinicaltrials.gov that evaluate the treatment of any psychiatric disorder with psychedelics (excluding ketamine) are summarized and analyzed. 70 registered studies were identified from a clinicaltrials.gov search on December 3, 2020. The majority of studies aim to investigate methylenedioxymethamphetamine (MDMA) (45.7%) and psilocybin (41.4%). Studies evaluating ayahuasca, lysergic acid diethylamide (LSD), ibogaine hydrochloride, salvia divinorum, 5-MeO-DMT and DMT fumarate were less common at 1.4%, 4.2%, 2.8%, 1.4%, 1.4% and 1.4% of total registered studies, respectively. Most of the studies on MDMA, psilocybin, ayahuasca and salvia divinorum investigated their therapeutic effect on post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). LSD was investigated for MDD, anxiety, and severe somatic disorders and ibogaine hydrochloride was investigated for substance and alcohol use disorders. 5-MeO-DMT and DMT fumarate were both investigated for MDD. Only 21/70 registered studies had published results with the majority not yet completed. In view of the large number of ongoing studies investigating psychedelics, it is imperative that these studies are considered by researchers and stakeholders in deciding the most relevant research priorities for future proposed studies.

The 2019 novel coronavirus pandemic, severe acute respiratory syndrome CoV-2 (COVID-19), has been a worldwide urgent public health threat, resulting in six-hundred seventy thousand deaths to date. The COVID-19 pandemic has led to a series of public health challenges. One such challenge is the management of diseases such as chronic neurological diseases during an epidemic event. COVID-19 affects all kinds of people, including older people with chronic underlying diseases, who are particularly at risk of severe infection or even death. Chronic neurological diseases such as epilepsy, dementia, Parkinson’s disease (PD), and multiple sclerosis (MS) are frequently associated with comorbidities; thus, these patients are in the high-risk category. Therefore, in this article, we review associations and challenges the people with epilepsy, dementia, PD, and MS faces during the COVID-19 pandemic and suggest approaches to provide consensus recommendations on how to provide the best possible care.