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Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

ABSTRACT: Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB.Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification.Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41).Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding.

SUBMITTER: Miller JM

PROVIDER: S-EPMC3725207 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

Miller Jeffrey M JM Hesselgrave Natalie N Ogden R Todd RT Sullivan Gregory M GM Oquendo Maria A MA Mann J John JJ Parsey Ramin V RV

Biological psychiatry 20130301 4

<h4>Background</h4>Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide ...[more]

PMID: 23453288

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Project description:Background:Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Methods:Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results:After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions:Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.

Project description:ImportanceMajor 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.ObjectiveUsing 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 participantsThis 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.InterventionPET scan.Main outcomes and measuresStriatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots.ResultsCompared 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 relevanceMajor 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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Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

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Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

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