Dopamine-induced pruning in monocyte-derived-neuronal-like cells (MDNCs) from patients with schizophrenia.

The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine's pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs. We also deepened the characterization of MDNCs by comparing its neurostructure to that of human developing neurons. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients' cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from medicated patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined and thus, needs to be considered as a confounder.

Alpha-lipoic acid in the treatment of psychiatric and neurological disorders: a systematic review.

Despite the existence of many preclinical studies, scientific evidence is lacking on the clinical use of alpha-lipoic acid (ALA) for central nervous system disorders. Therefore, we aimed at revising the literature concerning the use of ALA for the treatment of psychiatric and neurological conditions and to point out what is missing for the introduction of this antioxidant to this purpose. For this systematic review we performed a search using PubMed and SCOPUS databases with the following keywords: "alpha-Lipoic Acid AND central nervous system OR psychiatric disorders OR neurological disorders OR mood disorders OR anxiety OR psychosis OR Alzheimer OR Parkinson OR stroke". The total number of references found after automatically and manually excluding duplicates was 1061. After primary and secondary screening 32 articles were selected. Regarding psychiatric disorders, the studies of ALA in schizophrenia are advanced being ALA administration related to the improvement of schizophrenia symptoms and side effects of antipsychotic medication. In neurological disorders, ALA as a supplement was effective in the prevention of Alzheimer disease progression. For stroke, the use of the supplement ALAnerv® (containing 300 mg ALA) presented important results, since it was observed a reversal of clinical parameters and oxidative imbalance in these patients. For other neurological conditions, such as encephalopathy, multiple sclerosis, traumatic brain injury, mitochondrial disorders and migraine, the results are still preliminary. Overall, there is a need of well-designed clinical trials to enhance the clinical evidences of ALA effects for the treatment of neurological and psychiatric conditions.

Naltrexone in the Treatment of Broadly Defined Behavioral Addictions: A Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Broadly defined behavioral addiction is a conceptual framework including behaviors characterized by loss of control and continuation despite significant negative consequences. Broadly defined behavioral addictions share many similarities with substance use disorders. As naltrexone is one of the most studied treatment for substance use disorders, we conducted a meta-analysis of randomized placebo-controlled trials (RCT) assessing the effectiveness of naltrexone in the treatment of broadly defined behavioral addictions. METHOD: We conducted a literature search and selection, up to January 1, 2017, according to previously set inclusion criteria. The selected trials underwent a quality assessment before data extraction and statistical analysis, which used fixed and random effects models. Standardized mean differences (SMD) were calculated using Hedge's adjusted g. RESULTS: A total of 6 RCTs (n = 356) were included. Of these, 3 assessed naltrexone effectiveness in the treatment of pathological gambling, and 3 tested its benefits in broadly defined behavioral addictions other than pathological gambling (kleptomania, trichotillomania, and impulsive compulsive disorders). The meta-analysis of the whole sample resulted in a statistically significant score improvement under naltrexone versus placebo (fixed effect model: SMD = -0.27, 95% CI [-0.51 to -0.03], z = 2.23; p = 0.025). CONCLUSION: The results of our meta-analysis suggest a beneficial effect of naltrexone in the treatment of broadly defined behavioral addictions.

De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.

Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.

Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients. In contrast, we observed no de novo or truncating mutations in SYNGAP1 in samples from 142 subjects with autism spectrum disorders, 143 subjects with schizophrenia, and 190 control subjects. These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.

Incidence and outcomes of COVID-19 first wave pandemic in a French nursing home with residents suffering from severe mental illnesses.

During the first wave of COVID-19, nearly 50% of France's fatalities occurred in nursing homes. Older people with mental health disorders are considered to be more prone to infections when epidemics arise. To test this hypothesis, we conducted a retrospective descriptive and comparative study of the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a cohort of elderly residents with or without severe mental illness (SMI) living in a French nursing home facility. This was done during the first lockdown from March 17th until May 11th, 2020. Our study included 72 participants of 75 residents, of whom 58 contracted COVID-19, 14 developed a severe form requiring hospitalisation, and 14 died. The disease was significantly less frequent in residents with SMI 15(62%) than those without SMI 43 (89.6%). In regression analysis, a higher level of autonomy was significantly associated with a lower disease incidence. Once contracted, residents with or without SMI differed significantly neither on morbidity nor mortality. The period of survival did not either significantly differ between the two groups. As a potential explanation, we suggested that pathological social withdrawal added to stigmatisation could have protected SMI residents from contracting the disease.

Dosing antipsychotics in special populations of patients with schizophrenia: severe psychotic agitation, first psychotic episode and elderly patients.

Antipsychotic (AP) dosing is well established in nonelderly patients with acute exacerbations of schizophrenia, but not in special populations.This review describes the AP dosing procedures that have been used in clinical studies for acute psychotic agitation, a first episode of psychosis (FEP), and elderly patients. AP dosing data was extracted from the databases of drug regulatory authorities, and from clinical studies available in the medical literature. In acute psychotic agitation, intramuscular and oral APs are frequently prescribed in higher doses than those that saturate D2 receptors. Supersaturating doses of APs should be avoided due to an increased risk of adverse effects. In FEP, many studies showed efficacy of low doses of APs. Studies with risperidone and haloperidol suggested a dose reduction of approximately one third. Titration with a lower starting dose is recommended in elderly patients, due to possible decreases in pharmacokinetic clearance, and due to the risk of concomitant diseases and drug interactions. Exposure to some APs has been associated with QTc prolongation and arrhythmias, and a small but significant increase in the risk of stroke and mortality with APs has been seen, particularly in older people with dementia-related psychosis.

ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users.

ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Δ9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as ≥ 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC-COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population.

Neuroprotective evidence of alpha-lipoic acid and desvenlafaxine on memory deficit in a neuroendocrine model of depression.

Cognitive impairment is present in patients with depression. We hypothesized that alpha-lipoic acid (ALA) can reduce cognitive impairment, especially when combined to antidepressants. Female mice received vehicle or corticosterone (CORT) 20 mg/kg, s.c. for 14 days. From the 15th to 21st day, the animals were divided in groups: vehicle, CORT, CORT+desvenlafaxine (DVS) 10 or 20 mg/kg, ALA 100 or 200 mg/kg, DVS10+ALA100, DVS20+ALA100, DVS10+ALA200, or DVS20+ALA200. Tail suspension (TST), social interaction (SIT), novel object recognition (NOR), and Y-maze tests were conducted. Acetylcholinesterase activity (AChE) was measured in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). CORT caused depressive-like behavior, impairment in SIT, and cognitive deficits. Alpha-lipoic acid and DVS, alone or combined, reversed CORT effect on TST. In the NOR, ALA200 alone, DVS10+ALA100, or DVS10+ALA200 reversed the deficits in short-term memory, while DVS20 alone or DVS20+ALA200 reversed the deficits in long-term memory. In the Y-maze test, ALA200 alone, DVS20+ALA100, or DVS20+ALA200 reversed the deficits caused by CORT in the working memory. CORT increased AChE in the PFC, HC, and ST. ALA200 alone or DVS20+ALA200 reversed this effect in the PFC, while DVS20 or DVS20+ALA100 reversed this effect in the HC. In the ST, DVS10 or 20, alone or combined, and ALA100 reversed the effects of CORT. These results suggest that DVS+ALA, by reversing CORT-induced memory and social deficits, seems to be a promising therapy for the treatment of depression and reversal of cognitive impairment observed in this disorder.

Transdifferentiation of Human Circulating Monocytes Into Neuronal-Like Cells in 20 Days and Without Reprograming.

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are in vitro models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, n = 38,819 cells from 15 donors). To provide context and help researchers decide which in vitro model of neuronal development is best suited to address their scientific question,we compared our results with those of other in vitro models currently available and exposed advantages and disadvantages of each paradigm.

Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia.

BACKGROUND: Approximately 40% to 70% of neuroleptic-resistant schizophrenic patients are nonresponders to clozapine. Several clozapine augmentation strategies have come into clinical practice although often without evidence-based support. Among these strategies, the combined use of clozapine with another antipsychotic has been reported for up to 35% of patients receiving clozapine. OBJECTIVE: The purposes of the present work were to (1) review the available literature on the efficacy and safety of the clozapine augmentation with another antipsychotic using a MEDLINE search of the literature from 1978 to December 2005 and (2) to propose an operational definition of schizophrenia refractory to clozapine ("ultraresistant schizophrenia") for the implementation and homogenization of future therapeutic trials. CONCLUSION: Case controls and open clinical trials largely dominate the literature, and there are only 4 double-blind studies of clozapine augmentation with antipsychotics. The results of these studies are somewhat discrepant. Moreover, the heterogeneity of definitions of resistance to clozapine, of outcome measures and of dose and duration of pharmacological trials is a major limitation for drawing conclusions.

Somatic augmentation strategies in clozapine resistance--what facts?

BACKGROUND: Polypharmacy without evidence-based support is sometimes needed for patients treated with 40% to 70% clozapine who are clozapine nonresponders. Several somatic augmentation strategies are proposed in the scientific literature, with different levels of evidence for safety and efficacy. OBJECTIVES: The purpose of the present study is to review the available literature on the efficacy and safety of clozapine augmentation with somatic agents other than antipsychotics. The following classes of agents are considered: (1) mood stabilizers, (2) antidepressants, (3) electroconvulsive therapy and repetitive transcranial magnetic stimulation, (4) glutamatergic agents, (5)fatty acids supplements, and (6) benzodiazepines. RESULTS: Case controls and small-size clinical trials largely dominate the literature, limiting the power to draw conclusions concerning safety issues and the meaning of negative studies. Moreover, variable definitions of clozapine resistance, heterogeneous outcome measures, and short duration of treatment trials are additional limitations. CONCLUSION: Generally, adjunctive strategies for clozapine-resistant patients remain based on scarce evidence of efficacy and significant safety concerns. Low-frequency repetitive transcranial magnetic stimulation, fatty acids supplements, and mirtazapine showed good tolerability and some efficacy, but the results need replication.