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. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80 mg daily for 3 days), in chronic stable patients with schizophrenia (n = 26 analyzed). We focused on 3 T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p < 0.0001) and anterior cingulate/paracingulate (p = 0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r = -0.42, p = 0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism, which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment toward specific populations.

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. Treatment lasted for 28 days, and clinical efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scores. RESULTS: There were no significant differences between patients treated with AZD8529 versus placebo in change from baseline to endpoint in PANSS total, negative and positive symptom subscale, or CGI-S scores. In contrast, risperidone demonstrated significant efficacy relative to placebo. CONCLUSION: These results do not support a role for the mGluR-2 PAM AZD8529 as an antipsychotic and indicate that positive modulation of mGluR type 2 receptors alone is not sufficient for antipsychotic effects in acutely ill schizophrenia patients.

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. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated. RESULTS: The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments. CONCLUSIONS: An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce.

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]). Plasma samples of participants were assayed to determine levomilnacipran concentrations, and PK analyses were performed. Unbound plasma concentrations of levomilnacipran in MDD patients were estimated, and inhibitory concentration values were determined by curve fitting of the in vitro data. FINDINGS: Cmax and AUC were dose proportional after single dosing (25-100 mg) and multiple dosing (across the 25-300 mg dose range) of levomilnacipran ER in healthy subjects. Dose-proportional steady-state Cmax (93, 180, and 297 ng/mL) and AUC0-τ (1520, 2935, and 4799 ng*h/mL) were also observed in patients with MDD who received levomilnacipran ER (40, 80, and 120 mg daily). Tmax was ~6 hours and was similar after single and multiple oral doses of levomilnacipran ER. Estimates of levomilnacipran concentration at 50%, 80%, and 90% inhibition were 19, 91, and 237 nM, respectively, for the 5-HT transporter, and 10, 41, and 92 nM for the NE transporter. Average unbound plasma concentrations for levomilnacipran in MDD patients treated with levomilnacipran ER 40, 80, or 120 mg daily exceeded the estimated concentration at 80% and 90% inhibition for 5-HT and NE. IMPLICATIONS: Levomilnacipran PK was dose proportional after single and multiple dosing and was similar between healthy subjects and patients with MDD. Steady-state unbound plasma concentrations of levomilnacipran across the approved dose range (40, 80, and 120 mg daily) in MDD patients were estimated to be comparable or greater than the concentrations that inhibited reuptake of NE and 5-HT by >90% and >80%, respectively, in vitro.

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. METHODS AND RESULTS: Experiment 1: To assess the putative effects of genetic vulnerability without other confounds, 14 unaffected relatives of schizophrenia patients and 15 controls, all nonsmokers, were tested with/without 7 mg transdermal nicotine. Family members had reduced P50 amplitude to an initial auditory stimulus, but normal P50 gating. Nicotine decreased P50 amplitude in controls; family members had a mixed response: eight decreased and six increased P50 amplitude with nicotine. Experiment 2: To assess chronic nicotine use and short-term withdrawal as a model of nicotinic dysfunction, 26 healthy smokers (14 abstinent for >12 h) received 21 mg transdermal nicotine. Chronic nicotine use, alone, did not alter P50 amplitude or gating. Short-term withdrawal resulted in decreased P50 amplitude, with no effect on P50 gating. Nicotine increased P50 amplitude in abstinent smokers and decreased it in nonabstinent smokers. CONCLUSIONS: Familial vulnerability to schizophrenia reduces P50 amplitude. Nicotinic modulation of this deficit mirrors the effect of nicotine during smoking abstinence and suggests an "inverted-U" relationship between P50 amplitude and endogenous nicotinic activity. P50 amplitude may, therefore, be a sensitive marker of nicotinic dysfunction in individuals with familial risk for schizophrenia, which is mediated through mechanisms (e.g., α4ß2 receptors) that are distinct from those (e.g., α7 receptors) that mediate P50 gating.

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. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.

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. Recently, however, interest has increased in using computerized batteries for clinical trials. In this study, we tested 155 people with schizophrenia and 75 healthy control participants on both the MCCB and IntegNeuro, a touch-screen-based computerized battery with previously demonstrated high levels of reliability and validity, to determine comparability between test scores. In addition, we assessed test-retest reliability and practice effects over a one-month interval for both batteries and determined correlations between cognitive test scores and scores on functional outcome measures. High levels of agreement were observed between total battery composite scores (r > .80) and, in a canonical correlation analysis, between all critical single test scores from each battery (r(c) > .90). The batteries demonstrated essentially equivalent sensitivity in discriminating between patients and controls and equivalent levels of test-retest reliability and practice effects. Correlations between cognitive test scores and functional outcome measures were equivalent between the two batteries and low in nearly all cases. The number of missing data points was greater with IntegNeuro, highlighting the requirements for test administrator involvement even with computerized batteries.