TY - JOUR
AU - Cumming,, Paul
AB - This scientific commentary refers to ‘Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms’, by Avram et al. (doi:10.1093/brain/awz093). Increased dopamine transmission in striatum is a core feature in the ‘dopamine hypothesis of schizophrenia’, which was first proposed in the 1960s. Since then, PET studies with DOPA decarboxylase substrates such as 6-18F-fluoro-l-DOPA (18F-DOPA) have consistently shown increased dopamine synthesis capacity (DSC) in striatum of unmedicated patients with schizophrenia compared to healthy controls. However, elevated DSC may represent a trait marker for schizophrenia remaining stable regardless of psychopathology, disease phase, or medication status, or it may rather be a state marker of a protein disorder and thus amenable to modulation. In this issue of Brain, Avram and colleagues present the results of an ambitious 18F-DOPA PET study in a large group of medicated patients with schizophrenia, showing that those patients with remitted positive (but persisting negative) symptoms had a markedly reduced DSC in striatum, notably in the associative and sensorimotor divisions (Avram et al., 2019). The effect size of this reduction in DSC relative to findings in healthy controls (Hedges’ g 0.89) was of the same magnitude as the increase reported in meta-analyses of PET studies in untreated patients with schizophrenia (Howes et al., 2012). Tellingly, despite their substantial improvement in positive symptoms, the patients in the Avram et al. study had a distinct residual deficit in performing the Trail Making Test B; mediation analysis showed that reduced DSC mediated the cognitive difficulty. Similarly, we have previously shown that performance in tests of prefrontal cognitive function correlates positively with striatal DSC in healthy volunteers (Vernaleken et al., 2007), and that subchronic treatment with haloperidol downregulates DSC in patients with schizophrenia, relative to their own unmedicated baseline (Gründer et al., 2003). The new findings imply that patients with prolonged antipsychotic treatment may obtain their remission from positive symptoms at the cost of cognitive impairment, both being related to declining DSC. This clinically important implication raises new worries about the downsides of long-term treatment of patients with schizophrenia with dopamine D2/3 antagonists. However, the Avram et al. study is of cross-sectional design, and thus cannot establish if the relationship between cognitive deficits and lower DSC in patients is a consequence of their drug treatment or is an inherent aspect of remission per se. To resolve this might require a challenging study design with baseline and follow-up 18F-DOPA PET in groups of treated and untreated patients. The Avram et al. study benefits from having group sizes of 24, and a stable molecular imaging endpoint, i.e. the DSC calculated by linear graphic analysis relative to 18F-DOPA uptake in a cerebellum reference region, sometimes known as the Hartvig plot (Cumming, 2009) in recognition of the late Per Hartvig-Honoré, its first proponent. Avram et al. designate their metric as an influx constant kicer (min−1), but it might more properly be styled as a fractional rate constant, since there is no transfer of mass from cerebellum to the region of interest. Whatever one names it, the Hartvig slope is somehow an index of the local activity of DOPA decarboxylase, correlating with more physiologically precise parameters such as Ki, the net blood–brain clearance relative to the arterial input, or k3D, the relative activity of DOPA decarboxylase from compartmental analysis (Hoshi et al., 1993). As Avram et al. concede, the kicer is an imperfect measure of DSC due to its sensitivity to cerebral blood flow, uncorrected contamination of the brain signal from the plasma metabolite O-methyl-F-DOPA, and uncorrected loss of decarboxylated metabolites. Moreover, their claim that ‘DSC measured with 18F-DOPA is mainly a striatal measure, as reliability in the cortex seems to be poor’, holds truer for kicer than for the more physiologically defined measures noted above (Kumakura and Cumming, 2009). The trade-off between the convenient kicer analysis versus the technically more difficult arterial input methods lies at the heart of PET quantitation, and doubtless has some bearing on the discrepant 18F-DOPA PET results reported in the literature, as cited by Avram et al. A wide range of preclinical research has indicated that pharmacological blockade of dopamine D2/3 receptors acutely activates DSC in living striatum (Cumming, 2009), and we have seen a 20% increase in striatal 18F-DOPA-Ki in healthy volunteers exposed to haloperidol for 3 days, relative to their own baseline (Vernaleken et al., 2006). Acute stimulation of DSC stands in contrast to the decreased magnitude of 18F-DOPA-k3D seen in patients with subacute antipsychotic medication (Gründer et al., 2003), and likewise the cross-sectional finding of reduced kicer now reported by Avram et al. We have interpreted the phenomenon of late downregulation of DSC in human striatum to be consistent with depolarization block of nigrostriatal dopamine neurons, which is a cellular mechanism hitherto described in rats to explain the delayed response to treatment. Other supporting evidence for this downregulation in human brain is fragmentary and inconsistent. In one follow-up 18F-DOPA PET study, Jauhar et al. (2019) found no effect of medication on the magnitude of kicer, whereas Kim et al. (2017) found a decrease only in those patients receiving clozapine instead of first-line treatments. Completely discordant to the present report, McGowan et al. (2004) reported increased DSC among medicated patients compared to healthy control subjects, a difference comparable in magnitude to the elevated DSC seen in the meta-analyses of unmedicated patient studies. Although the patients in McGowan et al. were less well characterized than were the patients in the Avram et al. study, most likewise presented with similarly low positive symptoms. Among the other factors possibly contributing to the disparate 18F-DOPA PET findings are smoking status, carbidopa/entacapone pretreatment, and duration of treatment, dosage, and type of antipsychotic medication. There is certainly a lack of knowledge of differential effects of specific compounds on DSC, and a need for studies of follow-up design for assessing changes in DSC relative to own baseline. Figure 1 Open in new tabDownload slide A schematic diagram depicting the dopamine pathway in (A) healthy controls (B) untreated patients with schizophrenia, (C) upon acute treatment with an antipsychotic dopamine D2/3 receptor antagonist (pink symbols) and (D) chronic antipsychotic treatment, as assessed with 18F-DOPA PET. In this scenario, presynaptic autoreceptors normally exert (A) a strong tonic inhibition of dopamine synthesis and release. Conjecturally, autoreceptors are functionally uncoupled in (B) patients with schizophrenia, resulting in disinhibited dopamine synthesis, high tonic and/or phasic dopamine release, and excessive dopamine signalling at postsynaptic receptors (thick yellow arrows). Acute treatment with antipsychotic medication substantially blocks pre- and postsynaptic dopamine receptors (C), provoking disinhibition of the dopamine synthesis pathway. Despite substantial blockade of dopamine D2/3 receptors (60–80%), some dopamine signalling persists (thin yellow arrows). Chronic antipsychotic treatment maintains receptor blockade (D), despite possible upregulation of postsynaptic receptors (here increasing in number from three to four). However, the continuous antipsychotic treatment converts the dopamine neurons into a condition of depolarization block, in which dopamine synthesis and release decline. Figure 1 Open in new tabDownload slide A schematic diagram depicting the dopamine pathway in (A) healthy controls (B) untreated patients with schizophrenia, (C) upon acute treatment with an antipsychotic dopamine D2/3 receptor antagonist (pink symbols) and (D) chronic antipsychotic treatment, as assessed with 18F-DOPA PET. In this scenario, presynaptic autoreceptors normally exert (A) a strong tonic inhibition of dopamine synthesis and release. Conjecturally, autoreceptors are functionally uncoupled in (B) patients with schizophrenia, resulting in disinhibited dopamine synthesis, high tonic and/or phasic dopamine release, and excessive dopamine signalling at postsynaptic receptors (thick yellow arrows). Acute treatment with antipsychotic medication substantially blocks pre- and postsynaptic dopamine receptors (C), provoking disinhibition of the dopamine synthesis pathway. Despite substantial blockade of dopamine D2/3 receptors (60–80%), some dopamine signalling persists (thin yellow arrows). Chronic antipsychotic treatment maintains receptor blockade (D), despite possible upregulation of postsynaptic receptors (here increasing in number from three to four). However, the continuous antipsychotic treatment converts the dopamine neurons into a condition of depolarization block, in which dopamine synthesis and release decline. Our parsimonious explanation of the new results reported by Avram et al. is that the cohort of patients had indeed experienced downregulation of striatal DSC relative to their undocumented pre-medicated baseline condition, having entered into a condition analogous to the dopamine block seen in rats treated chronically with antipsychotic drugs. Our mentor, the late Arvid Carlsson, first suggested autoreceptors on midbrain dopamine neurons as potential targets for pharmacotherapy of schizophrenia. We suppose that a silver bullet for the perturbed dopamine system in schizophrenia might downregulate DSC without causing excessive blockade of postsynaptic dopamine receptors. The work presented by Avram et al. furnishes another piece in the puzzle of a better understanding of the regulation and dysregulation of dopamine systems in schizophrenia. Competing interests The authors report no competing interests. References Avram M , Brandl F , Cabello J , Leucht C , Scherr M , Mustafa M et al. . Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms . Brain 2019 ; 142 : 1813–26. WorldCat Cumming P . Imaging dopamine . Cambridge, UK : Cambridge University Press ; 2009 . Google Preview WorldCat COPAC Gründer G , Vernaleken I , Müller MJ , Davids E , Heydari N , Buchholz H-G et al. . Haloperidol down-regulates dopamine synthesis capacity in the brain of schizophrenic patients . Neuropsychopharmacology 2003 ; 28 : 787 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Hoshi H , Kuwabara H , Léger G , Cumming P , Guttman M , Gjedde A . 6-[18F]fluoro-L-DOPA metabolism in living human brain: a comparison of six analytical methods . J Cereb Blood Flow Metab 1993 ; 13 : 57 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat Howes OD , Kambeitz J , Kim E , Stahl D , Slifstein M , Abi-Dargham A et al. . The nature of dopamine dysfunction in schizophrenia and what this means for treatment . Arch Gen Psychiatry 2012 ; 69 : 776 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat Jauhar S , Veronese M , Nour MM , Rogdaki M , Hathway P , Natesan S et al. . The effects of antipsychotic treatment on presynaptic dopamine synthesis capacity in first-episode psychosis: a positron emission tomography study . Biol Psychiatry . 2019 ; 85 : 79 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Kim E , Howes OD , Veronese M , Beck K , Seo S , Park JW et al. . Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: an [18F]DOPA PET study . Neuropsychopharmacology . 2017 ; 42 : 941 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Kumakura Y , Cumming P . PET studies of cerebral levodopa metabolism; A review of clinical findings and modeling approaches [Invited review] . Neuroscientist 2009 ; 15 : 635 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat McGowan S , Lawrence AD , Sales T , Quested D , Grasby P . Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study . Arch Gen Psychiatry . 2004 ; 61 : 134 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat Vernaleken I , Buchholz HG , Kumakura Y , Siessmeier T , Stoeter P , Bartenstein P et al. . ‘Prefrontal’ cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation . Hum Brain Mapp . 2007 ; 28 : 931 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Vernaleken I , Kumakura Y , Cumming P , Buchholz H-G , Gründer G . Modulation of [18F]-FDOPA kinetics in brain of healthy volunteers after acute challenge with haloperidol . Neuroimage 2006 ; 30 : 1332 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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TI - The downside of downregulation
JF - Brain
DO - 10.1093/brain/awz133
DA - 2019-06-01
UR - https://www.deepdyve.com/lp/oxford-university-press/the-downside-of-downregulation-HUphiQkAq5
SP - 1500
VL - 142
IS - 6
DP - DeepDyve
ER -