Peripheral signature of altered synaptic integrity in young onset cannabis use disorder: A proteomic study of circulating extracellular vesicles.

Background: Rates of Cannabis Use Disorder (CUD) are highest amongst young adults. Paucity of brain tissue samples limits the ability to examine the molecular basis of cannabis related neuropathology. Proteomic studies of neuron-derived extracellular vesicles (NDEs) isolated from the biofluids may reveal markers of neuropathology in CUD.

Age, gender and body-mass-index relationships with in vivo CB receptor availability in healthy humans measured with [C]OMAR PET.

Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18-55 years; 44 male; BMI=27.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

Importance: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.

Objective: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD.

Design, Setting, And Participants: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study.

In vivo evidence for β2 nicotinic acetylcholine receptor subunit upregulation in smokers as compared with nonsmokers with schizophrenia.

Background: Schizophrenia is associated with very high rates of tobacco smoking. The latter may be related to an attempt to self-medicate symptoms and/or to alterations in function of high-affinity β2-subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs).

Methods: Smoking and nonsmoking subjects with schizophrenia (n=31) and age-, smoking-, and sex-matched comparison subjects (n=31) participated in one [123I]5-IA-85380 single photon emission computed tomography scan to quantify β2*-nAChR availability.

Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia.

Cognitive impairment is known to be a core deficit in schizophrenia. Existing treatments for schizophrenia have limited efficacy against cognitive impairment. The ubiquitous use of nicotine in this population is thought to reflect an attempt by patients to selfmedicate certain symptoms associated with the illness.

Effect of a nicotine vaccine on nicotine binding to β2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers.

Objective: Nicotine promotes smoking partly by binding to β2-containing nicotinic acetylcholine receptors (β2*-nAChRs) in the brain. Smoking one tobacco cigarette results in occupation of 80% of β2*-nAChRs for more than 6 hours. This likely contributes to maintenance of smoking dependence and cessation difficulty.

Acute effects of THC on time perception in frequent and infrequent cannabis users.

Rationale: Cannabinoids have been shown to alter time perception, but existing literature has several limitations. Few studies have included both time estimation and production tasks, few control for subvocal counting, most had small sample sizes, some did not record subjects' cannabis use, many tested only one dose, and used either oral or inhaled administration of Δ⁹-tetrahydrocannabinol (THC), leading to variable pharmacokinetics, and some used whole-plant cannabis containing cannabinoids other than THC. Our study attempted to address these limitations.

Preliminary findings on the interactive effects of IV ethanol and IV nicotine on human behavior and cognition: a laboratory study.

Introduction: There are mixed reports on nicotine's effects on alcohol-induced impairment in cognitive performance and behavior in humans. The main objective of this study was to characterize the interactive effects of acute intravenous (IV) alcohol and nicotine administration on behavior and cognition in healthy nonsmokers.

Methods: Healthy subjects aged 21-44 years participated in 3 test days.

Clinical significance of neurological soft signs in schizophrenia: factor analysis of the Neurological Evaluation Scale.

Background: Nonlocalizing neurologic deficits detectable by clinical evaluation-"soft signs"-are a robust finding in patients diagnosed with schizophrenia, but their conceptual and neuroanatomical correlates remain unclear. The purpose of this study was to evaluate the organization of these deficits and their clinical correlates using the Neurological Evaluation Scale (NES).

Methods: Ninety-three male veterans with schizophrenia and schizoaffective disorder were evaluated using a detailed clinical assessment that included the NES, the Extrapyramidal Symptom Rating Scale, the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale, the Positive and Negative Syndrome Scale, the Wisconsin Card Sorting Test (WCST), the Schedule for the Deficit Syndrome (SDS), and the Digit Symbol Substitution Task (DSST).

Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists.

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials.

High dose D-serine in the treatment of schizophrenia.

Background: D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day).

Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia.

Current treatments for psychiatric disorders were developed with the aim of providing symptomatic relief rather than reversing underlying abnormalities in neuroplasticity or neurodevelopment that might contribute to psychiatric disorders. This review considers the possibility that psychiatric treatments might be developed that target neuroplasticity deficits or that manipulate neuroplasticity in novel ways. These treatments might not provide direct symptomatic relief.

Absence of significant interactive effects of high-dose D-cycloserine and ethanol in healthy human subjects: preliminary insights into ethanol actions at the glycine B site of NMDA glutamate receptors.

Background: Ethanol reduces N-methyl-d-aspartate (NMDA) glutamate receptor function via multiple cellular targets. It is not yet clear whether direct ethanol antagonism of the glycine(B) co-agonist site of NMDA receptors is relevant to this effect. The purpose of this study was to evaluate whether ethanol effects at the glycine(B) co-agonist site was clinically relevant by evaluating some aspects of the psychopharmacologic interactions between the glycine(B) partial agonist, D-cycloserine (DCS), and ethanol in healthy human subjects.

Psychiatric safety of ketamine in psychopharmacology research.

Rationale: A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of subanesthetic doses of ketamine in experimental psychopharmacology studies.

Objective: To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset.

The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia.

Individuals with schizophrenia are at increased risk for developing substance abuse disorders. Here, we consider factors that might elevate their risk for substance abuse. The tendency among schizophrenic individuals to overvalue drug-like rewards and to devalue the potential negative consequences of substance abuse may be a contributing factor to their substance abuse risk.

Cerebral metabolic effects of intravenous glycine in healthy human subjects.

Enhancing N-methyl-D-aspartate (NMDA) receptor function via increasing synaptic concentrations of glycine is currently investigated as a novel approach to treat schizophrenia. The neural correlates of enhanced NMDA receptor function in humans, however, are unclear to date. The present study determines the effects of intravenous administration of the glycine on regional cerebral metabolic rate of glucose (rCMRGlu) in healthy control subjects by using [18F]fluorodeoxyglucose and positron emission tomography and on neuropsychological behavioral measures.

Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function.

Background: In healthy individuals, ketamine hydrochloride and amphetamine sulfate produce cognitive, behavioral, and subjective effects resembling endogenous psychoses. Studying the comparative and interactive effects of these agents may provide insights into the roles of the glutamate and monoamine systems in psychosis and cognition.

Objectives: To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals.

Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects.

Rationale: Some of the behavioral consequences of deficits in N-methyl-D-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry.

Objective: This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects.

Methods: Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.

Nicotine effects on brain function and functional connectivity in schizophrenia.

Background: Nicotine in tobacco smoke can improve functioning in multiple cognitive domains. High rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Our primary aim was to determine whether nicotine improves cognitive function by facilitating activation of brain regions mediating task performance or by facilitating functional connectivity.

NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy.

This paper reviews clinical evidence suggesting that antagonism of the N-methyl-D-aspartate subtype of glutamate receptors by ethanol may convey an important component of the ethanol intoxication signal, that is, subjective and objective responses associated with the consumption of a large amount of ethanol. It will then review recent evidence that two phenotypes associated with increased risk for heavy alcohol consumption, recovering ethanol-dependent patients, and healthy individuals with a family history of alcohol dependence, exhibit reduced sensitivity to the dysphoric consequences of administration of the NMDA receptor antagonist, ketamine. Each of these groups displays reduced sensitivity to a potentially important response that might normally trigger the cessation of ethanol consumption.

NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development.

There is an urgent need to improve the pharmacotherapy of schizophrenia despite the introduction of important new medications. New treatment insights may come from appreciating the therapeutic implications of model psychoses. In particular, basic and clinical studies have employed the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine, as a probe of NMDA receptor contributions to cognition and behavior.

Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.

Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine.

N-methyl-D-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability.

This review takes a translational neuroscience perspective on the role of glutamate systems in human ethanol abuse and dependence. Ethanol is a simple molecule with profound effects on many chemical systems in the brain. Glutamate is the primary excitatory neurotransmitter in the brain.