Proof-of-Mechanism Study of the Phosphodiesterase 10 Inhibitor RG7203 in Patients With Schizophrenia and Negative Symptoms.

Background: Reduced activation of dopamine D receptor signaling may be implicated in reward functioning as a potential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highly expressed in the striatum, modulates both dopamine D- and D-dependent signaling.

Methods: We assessed whether augmentation of D signaling by the PDE10 inhibitor RG7203 enhances imaging and behavioral markers of reward functions in patients with schizophrenia and negative symptoms.

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D receptor positive allosteric modulator in patients with schizophrenia.

ASP4345, a novel dopamine D receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials.

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

Background: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D) receptor that selectively binds to, and enhances the activity of, D receptors.

A Proof-of-Concept Study Evaluating the Phosphodiesterase 10A Inhibitor PF-02545920 in the Adjunctive Treatment of Suboptimally Controlled Symptoms of Schizophrenia.

Background: Effective treatments for managing suboptimal clinical responses to current therapy for schizophrenia remain a critical unmet need. Phosphodiesterase 10A (PDE10A) inhibition represents a mechanistically novel approach to the treatment of schizophrenia, with preclinical studies suggesting improvements in partially responsive symptoms could be achieved via adjunctive use of the PDE10A inhibitor PF-02545920. Therefore, the adjunctive safety, tolerability, pharmacokinetics, and efficacy of multiple repeat doses of PF-02545920 were investigated in a phase 1b study and subsequent phase 2 study.

A Randomized Multiple Dose Pharmacokinetic Study of a Novel PDE10A Inhibitor TAK-063 in Subjects with Stable Schizophrenia and Japanese Subjects and Modeling of Exposure Relationships to Adverse Events.

Background: Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons of the striatum. TAK-063 is a selective inhibitor of PDE10A in clinical development for the treatment of schizophrenia.

Objectives: Safety, tolerability, and pharmacokinetics (PK) of TAK-063 were evaluated following multiple rising oral doses, and PK/adverse event (AE) models were developed to characterize the relationship between TAK-063 exposure and incidence of specific AEs.

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.

Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.

To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1-6; days, 1-5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21).

Use of translational pharmacodynamic biomarkers in early-phase clinical studies for schizophrenia.

Schizophrenia is a severe mental disorder characterized by cognitive deficits, and positive and negative symptoms. The development of effective pharmacological compounds for the treatment of schizophrenia has proven challenging and costly, with many compounds failing during clinical trials. Many failures occur due to disease heterogeneity and lack of predictive preclinical models and biomarkers that readily translate to humans during early characterization of novel antipsychotic compounds.

The H3 antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers.

Aims: ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia.

Response to citalopram is not associated with SLC6A4 genotype in African-Americans and Caucasians with major depression.

Aims: Ethnic differences in genotype frequency provide a natural condition for assessing the contribution of gene variations to the causes and treatments of disease. Accordingly, the purpose of this study was to determine whether ethnic variations in allele frequencies of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) of the SLC6A4 gene were related to the response to the treatment of depression.

Main Methods: African-Americans (n=101) and Caucasians (n=100) with major depressive disorder were treated with the antidepressant citalopram (20-60mg/day) for 8weeks.

Open-label, randomized, parallel-group controlled clinical trial of massage for treatment of depression in HIV-infected subjects.

Objectives: The study objectives were to determine whether massage therapy reduces symptoms of depression in subjects with human immunodeficiency virus (HIV) disease.

Design: Subjects were randomized non-blinded into one of three parallel groups to receive Swedish massage or to one of two control groups, touch or no intervention for eight weeks.

Settings/location: The study was conducted at the Department of Psychiatry and Behavioral Neurosciences at Cedars-Sinai Medical Center in Los Angeles, California, which provided primary clinical care in an institutional setting.

Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.

Org 26576 acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. The aim of this Phase 1b study (N=54) was to explore safety, tolerability, pharmacokinetics, and pharmacodynamics of Org 26576 in depressed patients. Part I (N=24) evaluated the maximum tolerated dose (MTD) and optimal titration schedule in a multiple rising dose paradigm (range 100 mg BID to 600 mg BID); Part II (N=30) utilized a parallel groups design (100 mg BID, 400 mg BID, placebo) to examine all endpoints over a 28-day dosing period.

Maximum tolerated dose evaluation of the AMPA modulator Org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase II dose selection.

Background: A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials.

Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder.

Objective: The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo (olive oil) in the initial treatment of individuals with major depressive disorder (MDD). We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response.

Methods: Forty-two subjects participated in this 9-week randomized, masked, placebo-controlled study of combination therapy (two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid, 200 mg of and docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) treatment of MDD.

Effect of bupropion on nocturnal urinary free cortisol and its association with antidepressant response.

The study examined the relationship between pre-treatment nocturnal hypothalamic-pituitary-adrenal (HPA) activity, as reflected by nocturnal urinary free cortisol (NUFC) response to a single-dose of sustained-release bupropion, and the antidepressant effect of the drug. NUFC changes in response to treatment with bupropion also were assessed. NUFC was measured in 20 patients with unipolar major depressive disorder before and after initiating treatment with sustained-release bupropion.

Effect of treatment with bupropion on EEG sleep: relationship to antidepressant response.

The objective of this study was to assess whether treatment with sustained-release bupropion (Wellbutrin-SR) produces alterations in electroencephalographic (EEG) sleep that are associated with clinical response to the drug. EEG sleep was measured in 20 patients with unipolar major depressive disorder before and after treatment with sustained-release bupropion. Each EEG sleep session consisted of two consecutive nights.