dihydrexidine and Schizophrenia

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D

Topics: Animals; Dopamine; Dopamine Agonists; Dopamine Antagonists; Humans; Phenanthridines; Prefrontal Cortex; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology

Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ.. We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint.. There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS.. These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.

Topics: Adult; Antipsychotic Agents; Attention; Cerebral Cortex; Cognition; Cognition Disorders; Dopamine; Dopamine Agonists; Double-Blind Method; Female; Humans; Male; Memory, Short-Term; Neuropsychological Tests; Nootropic Agents; Phenanthridines; Psychiatric Status Rating Scales; Receptors, Dopamine D1; Schizophrenia

The potential of dopamine D(1) receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D(1) agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18-65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D(1)-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements.

Topics: Adult; Antipsychotic Agents; Brain; Cross-Over Studies; Dopamine Agonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Image Processing, Computer-Assisted; Injections, Subcutaneous; Magnetic Resonance Imaging; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Oxygen; Phenanthridines; Pilot Projects; Psychiatric Status Rating Scales; Receptors, Dopamine D1; Regional Blood Flow; Schizophrenia; Treatment Outcome

Dopamine D1 receptors play an important role in memory and cognition in non-human primates. Dopamine D1 agonists have been shown to reverse performance deficits in both aged non-human primates and in primates with lesions to dopamine systems. This study explored whether a single dose of the first full D1 agonist dihydrexidine (DAR-0100) would cause changes in brain activity (perfusion) in dopamine-rich brain regions. We used a new gadolinium-contrast magnetic resonance perfusion scanning technique to measure brain activity. A within-subject cross-over double-blind randomized design was used in 20 adults with SCID-diagnosed schizophrenia. Each morning at 0800 h, they were scanned on a 3.0 T MRI scanner for perfusion. They then received either 20 mg of dihydrexidine, or placebo, subcutaneously over 15 min. Over the next 45 min, they had intermittent MRI scans. Two days later, they had a repeat of the Day 1 schedule, but received the opposite treatment from that given on the first day. Within-day, as well as between-day, comparisons were made to test for perfusion effects of dihydrexidine. Analysis revealed that dihydrexidine induced a significant increase in both prefrontal and non-prefrontal perfusion compared to placebo. The greatest increases occurred approximately 20 min after dihydrexidine infusion, consistent with the short pharmacokinetic half-life of dihydrexidine. These data are consistent with the hypothesis formulated from studies of non-human primates that dihydrexidine and other D1 agonists may be able to modulate prefrontal dopaminergic function.

Topics: Adult; Cerebrovascular Circulation; Contrast Media; Cross-Over Studies; Dopamine Agonists; Dose-Response Relationship, Drug; Double-Blind Method; Functional Laterality; Humans; Magnetic Resonance Imaging; Phenanthridines; Prefrontal Cortex; Receptors, Dopamine D1; Schizophrenia; Time Factors

The 2016 Schizophrenia International Research Society (SIRS) Conference, held in Florence, Italy, attracted approximately 1,800 attendees from over 54 countries to the stately Firenze Fiera Conference Center from April 2-6, 2016. Providing plenary sessions, special sessions, symposia, workshops, oral presentations and poster presentations, this 5th Biennial SIRS Conference focused on "Deconstructing Schizophrenia towards Targeted Treatment." In conjunction with the Schizophrenia Research Forum, a Web project of the Brain and Behavior Research Foundation, and with our thanks to the SIRS organizers and staff, we bring you the following selected highlights.

Topics: Animals; Antipsychotic Agents; Cognition; Critical Period, Psychological; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Fatty Acids, Omega-3; Humans; Neostriatum; Pharmacogenetics; Phenanthridines; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Vitamin D Deficiency