JAMA Psychiatry

2019 May 1. doi: 10.1001/jamapsychiatry.2019.0801

Pizzagalli DA^1,2, Berretta S^1,2, Wooten D^1,3, Goer F², Pilobello KT², Kumar P^1,2, Murray L², Beltzer M², Boyer-Boiteau A², Alpert N^1,3, El Fakhri G^1,3, Mechawar N⁴, Vitaliano G^1,2, Turecki G⁴, Normandin M^1,3

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.