Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder

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 ([ 11 C] 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.

Hopelessness, Dissociative Symptoms, and Suicide Risk in Major Depressive Disorder: Clinical and Biological Correlates

“…It is often used as a target for the evaluation of dopaminergic circuit efficiency [15]. Using peculiar radiotracers for DAT, single-photon emission computerized tomography (SPECT) has been extensively used in MDD patients and has shown an important reduction in DAT availability in subcortical regions as result of a striatal dopaminergic dysfunction [16][17][18]. In particular, several studies have focused on the roles of this dysfunction in anhedonic patients with MDD by following the hypothesis of a cortico-striatal-limbic dopaminergic dysfunction, involving selected areas of ventral (nucleus accumbens) and dorsal (putamen, caudate) striatum, in which the reward system seems to play a crucial role [19,20].…”

Depression genetic risk score is associated with anhedonia-related markers across units of analysis

“…Mounting evidence implicates dorsal and ventral striatal regions in the pathophysiology of and increased vulnerability to depression. First, hemodynamic, structural and molecular imaging studies have reported abnormalities in both the NAc and putamen in MDD as well as unaffected offspring of parents with MDD 27,58,71–74 . Second, structural MRI studies have linked smaller dorsal striatum to anhedonic symptoms among healthy samples 26,28 .…”

Psychological and neurobiological aspects of suicide in adolescents: Current outlooks

“…Dopamine (DA), a catecholamine synthesized in a two-step reaction process that involves the conversion of tyrosine into L-DOPA, a reaction catalyzed by the tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis ( Nagatsu, 1991 ). In recent years, several reports describe a good correlation between dysfunction of dopaminergic functioning and suicide ( Fitzgerald et al., 2017 ; Ho et al., 2018 ; Oquendo et al., 2014 ; Pizzagalli et al., 2019 ). The analysis of key dopaminergic markers such as the dopamine transporter (DAT) and dopamine receptors D1 and D2 revealed an imbalance in the D1 and D2 abundance in the dorsal striatum in suicide compared to controls, and a clear reduction in the amount of DAT and D1 appeared with age.…”