title: Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions.
abstract: Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D2receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D2receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [15O]-water and [18F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Daniel Paul
authors.initials: DP
authors.lastname: Eisenberg
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Yankowitz
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Ianni
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Dani Y
authors.identifier: http://orcid.org/0000-0002-6292-7392
authors.initials: DY
authors.lastname: Rubinstein
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Kohn
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Hegarty
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gregory
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Apud
authors.affiliation: Section on Integrative Neuroimaging, Clinical &Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Karen F
authors.initials: KF
authors.lastname: Berman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010104:Oxygen Radioisotopes / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy* / Q000473:pathology*; D018709:Statistics, Nonparametric; D014867:Water / Q000494:pharmacology; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D010104:Oxygen Radioisotopes; C000615263:Oxygen-15; D014867:Water; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; D004298:Dopamine