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Original Investigation
May 1, 2019

Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence

Author Affiliations
  • 1Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
  • 2McLean Hospital, Belmont, Massachusetts
  • 3Department of Radiology, Harvard Medical School, Boston, Massachusetts
  • 4McGill Group for Suicide Studies, Douglas Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
JAMA Psychiatry. 2019;76(8):854-861. doi:10.1001/jamapsychiatry.2019.0801
Key Points

Question  Are individuals with major depressive disorder who are not taking medication characterized by lower dopamine transporter levels within the brain reward system compared with psychiatrically healthy control participants?

Findings  In this cross-sectional study that analyzed positron emission tomography in 25 individuals with major depressive disorder and 23 healthy controls and postmortem data in 15 individuals with major depressive disorder and 14 healthy controls, major depressive disorder was linked to lower dopamine transporter levels in the dorsal striatum. In the imaging data, this dysfunction was exacerbated by more episodes of depression.

Meaning  Decreased dopamine transporter availability might represent a compensatory downregulation because of low dopaminergic signaling within mesolimbic pathways.

Abstract

Importance  Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive.

Objective  Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide.

Design, Setting, and Participants  This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered.

Intervention  PET scan.

Main Outcomes and Measures  Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots.

Results  Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, −0.62 to −0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, −0.92 to −1.15).

Conclusions and Relevance  Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.

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