Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia.

Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy.

AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: A proof of principle study.

Introduction: Activation of metabotropic glutamate (mGluR2/3) receptors has been proposed as an alternative mechanism to dopaminergic-based antipsychotics to correct glutamatergic deficits hypothesized to underlie schizophrenia symptoms. This study investigates the efficacy and safety of AZD8529, a selective positive allosteric modulator (PAM) at the mGlu2 receptor, in symptomatic patients with schizophrenia.

Methods: Patients were randomized to receive AZD8529 40 mg, risperidone 4 mg, or placebo as monotherapy.

Levomilnacipran Pharmacokinetics in Healthy Volunteers Versus Patients with Major Depressive Disorder and Implications for Norepinephrine and Serotonin Reuptake Inhibition.

Purpose: Levomilnacipran, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is approved for the treatment of major depressive disorder (MDD) in adults. The objectives of this investigation were to characterize the pharmacokinetic (PK) parameters of levomilnacipran in healthy subjects and in patients with MDD and to compare the plasma concentrations observed at clinically effective doses (40-120 mg daily) in MDD patients versus in vitro inhibitory concentration values for NE and 5-HT transporters.

Methods: Data from 2 trials were analyzed: a Phase I trial (healthy volunteers received a single dose of levomilnacipran extended-release capsule [ER; 25, 50, or 100 mg], escalating multiple doses of levomilnacipran ER [25-300 mg once daily], or placebo); and a Phase III trial (adults with MDD received a fixed dose of levomilnacipran ER [40, 80, or 120 mg once daily for 8 weeks]).

A novel once-daily fixed-dose combination of memantine extended release and donepezil for the treatment of moderate to severe Alzheimer's disease: two phase I studies in healthy volunteers.

Background: Combining two standard-of-care medications for Alzheimer's disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake.

Methods: Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals.

Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.

Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex.

P50 amplitude reduction: a nicotinic receptor-mediated deficit in first-degree relatives of schizophrenia patients.

Rationale: Impaired P50 gating is a putative index of genetically mediated nicotinic dysfunction in schizophrenia. However, assessment is confounded, in patients, by differential effects of smoking, symptoms, and treatment.

Objectives: This double-blind placebo-controlled study was designed to tease apart the relationships among P50, acute and chronic nicotine exposure, and familial risk.

A comparative study of the MATRICS and IntegNeuro cognitive assessment batteries.

Cognitive impairment is prevalent in schizophrenia and is related to poorer functional and treatment outcomes. Cognitive assessment is therefore now a routine component of clinical trials of new treatments for schizophrenia. The current gold-standard for cognitive assessment in clinical trials for schizophrenia is the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB), which was developed based on expert consensus and incorporates paper-and-pencil tests (and one computerized measure) with an established history in the field of neuropsychology.