title: A single 20 mg dose of dihydrexidine (DAR-0100), a full dopamine D1 agonist, is safe and tolerated in patients with schizophrenia.
abstract: 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.
authors.affiliation: Brain Stimulation Laboratory (BSL), Psychiatry Department, Medical University of South Carolina (MUSC) 29425, United States. georgem@musc.edu
authors.forename: Mark S
authors.initials: MS
authors.lastname: George
authors.forename: Christine E
authors.initials: CE
authors.lastname: Molnar
authors.forename: Emily L
authors.initials: EL
authors.lastname: Grenesko
authors.forename: Berry
authors.initials: B
authors.lastname: Anderson
authors.forename: Qiwen
authors.initials: Q
authors.lastname: Mu
authors.forename: Kevin
authors.initials: K
authors.lastname: Johnson
authors.forename: Ziad
authors.initials: Z
authors.lastname: Nahas
authors.forename: Michael
authors.initials: M
authors.lastname: Knable
authors.forename: Prabhavathi
authors.initials: P
authors.lastname: Fernandes
authors.forename: Jorge
authors.initials: J
authors.lastname: Juncos
authors.forename: Xuemei
authors.initials: X
authors.lastname: Huang
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.forename: Richard B
authors.initials: RB
authors.lastname: Mailman
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D018592:Cross-Over Studies; D018491:Dopamine Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007279:Injections, Subcutaneous; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood*; D010617:Phenanthridines / Q000008:administration & dosage* / Q000009:adverse effects; D010865:Pilot Projects; D011569:Psychiatric Status Rating Scales; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D010617:Phenanthridines; D017447:Receptors, Dopamine D1; C061532:dihydrexidine; D010100:Oxygen