Molecular tools for assessing human depression by positron emission tomography (original) (raw)
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Molecular Neurobiology of Depression: PET Findings on the Elusive Correlation with Symptom Severity
Frontiers in Psychiatry, 2013
Molecular mechanisms in the brain are assumed to cause the symptoms and severity of neuropsychiatric disorders. This review concerns the elusive nature of relationships between the severity of depressive disorders and neuromolecular processes studied by positron emission tomography (PET). Recent PET studies of human depression have focused on serotonergic, dopaminergic, muscarinic, nicotinic, and GABAergic receptors, as well as central processes dependent on monoamine oxidase, phosphodiesterase type 4, amyloid plaques, neurofibrillar tangles, and P-glycoprotein. We find that reliable causal links between neuromolecular mechanisms and relief from depressive disorders have yet to be convincingly demonstrated. This situation may contribute to the currently limited use of PET for exploring the neuropathways that are currently viewed as being responsible for beneficial effects of antidepressant treatment regimes.
Biological Psychiatry, 2009
ABSTRACT BACKGROUND: 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 [11C]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, [11C]DASB. METHODS: Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [11C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. RESULTS: 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). CONCLUSIONS: 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.
PET brain imaging with 11CMcN5652 shows increased serotonin transporter availability in major depression
Journal of Affective Disorders, 2004
Background: Alterations in the brain serotonin (5-HT) system have been found in patients with depression. We used the selective 5-HT transporter site ligand [ 11 C](+)McN5652 and positron emission tomography (PET) to examine the hypothesis that alterations in 5-HT transporter levels may be present in selected regions of the brain in depressed patients. Methods: Four drug free depressed patients and four healthy control subjects were studied using [ 11 C](+)McN5652 and PET. The distribution volume (DV) ratio of the PET ligand in selected regions of interest (ROIs) compared to cerebellum were calculated for the ROIs. Results: Patients showed significantly larger DV ratios in the left frontal cortex ( P = 0.013) and right cingulate cortex ( P = 0.043) compared to control subjects. Limitation: The sample size was modest with gender differences between the subject groups. The PET agent, [ 11 C](+)McN5652, may have a lower binding affinity for the 5-HT transporter in the cortical regions compared to other brain regions. Conclusion: These findings suggest that 5-HT transporter sites may be increased in the frontal and cingulate cortices of depressed patients. These alterations in 5-HT transporter sites may be of pathophysiologic significance in the etiology of depression and its treatment. D
Neuroreceptor imaging in depression
Neurobiology of Disease, 2013
The in vivo study of receptor binding potential in the human brain is made possible by positron emission tomography (PET) imaging. Here we review PET studies of neuroreceptor function in mood disordersspecifically, major depressive disorder (MDD) and bipolar disorder (BD). We concentrate on the most widely studied receptors of the serotonergic and dopaminergic systems. Specifically, the serotonin 1A (5-HT 1A), serotonin 2A (5-HT 2A), serotonin 1B (5-HT 1B), dopamine 1 (D1), and dopamine 2/3 (D2/3) receptors. We also review PET studies of the serotonin transporter (5-HTT), the dopamine transporter (DAT), monoamine oxidase A (MAO-A), and the muscarinic 2 receptor (M2). On the basis of the PET literature as well as supporting genetic studies, postmortem data, and preclinical models of depression, and several models of how monoaminergic function is altered in mood disorders are discussed with respect to inflammation, endocrine dysfunction, depression subtypes, and altered neurocircuitry.
Molecular imaging for depressive disorders
AJNR. American journal of neuroradiology, 2014
Molecular imaging is the visualization, characterization, and measurement of biologic processes at the molecular and cellular levels in humans and other living systems. Molecular imaging techniques such as MR spectroscopy and PET have been used to explore the molecular pathophysiology of depression and assess treatment responses. MR spectroscopy is a noninvasive technique that assesses the levels of biochemical metabolites in the brain, while PET uses radioligands injected in the bloodstream that have high binding affinity for target molecules. MR spectroscopy findings suggest a role for glutamate/glutamine and gamma-aminobutyric acid in depression. PET has generally failed to find a correlation between radioligand binding potential and depression severity or treatment response, though it may offer promise in distinguishing responders and nonresponders to treatment. A major challenge for both modalities is that depression is a heterogeneous, multifactorial disorder, while MR spectro...
Biological Psychiatry, 1998
Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [ 123 I]-CIT SPECT and platelet [ 3 H]paroxetine binding. Methods: Drug-free depressed and healthy subjects were injected with 211 Ϯ 22 MBq [ 123 I]-CIT and imaged 24 Ϯ 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V 3 Љ ϭ (brainstem-occipital)/ occipital), a measure proportional to the binding potential (B max /K d ), was used for all comparisons. Results: Results showed a statistically significant reduction in brainstem V 3 Љ values in depressed as compared to healthy subjects (3.1 Ϯ .9 vs. 3.8 Ϯ .8, p ϭ .02). Platelet [ 3 H]paroxetine binding was not altered (B max ϭ 2389 Ϯ 484 vs. 2415 Ϯ 538 fmol/mg protein, p ϭ .91) and was not significantly correlated with brainstem [ 123 I]- CIT binding (r ϭ Ϫ0.14, p ϭ .48). Conclusions: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2015
Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). The study aimed to examine whether the pretreatment SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcome to SERT-targeted antidepressants. We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3....
Movement disorders : official journal of the Movement Disorder Society, 2008
This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [(11)C]DASB. Depressed PD patients displayed a wide-spread increase (8-68%) in [(11)C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [(11)C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[(11)C]DASB findings in major depression, the present preliminary data suggest that increased [(11)C]DASB binding, possibly reflecting greater serotonin transporter density (up-regulation), might be a pathological feature of depression in Par...
Pet imaging of serotonin 1A receptor binding in depression
Biological Psychiatry, 1999
The serotonin-1A (5HT1A) receptor system has been implicated in the pathophysiology of major depression by postmortem studies of suicide victims and depressed subjects dying of natural causes. This literature is in disagreement, however, regarding the brain regions where 5HT1A receptor binding differs between depressives and controls and the direction of such differences relative to the normal baseline, possibly reflecting the diagnostic heterogeneity inherent within suicide samples. PET imaging using the 5HT1A receptor radioligand, [ 11 C]WAY-100635, may clarify the clinical conditions under which 5HT1A receptor binding potential (BP) is abnormal in depression. Methods: Regional 5HT1A receptor BP values were compared between 12 unmedicated depressives with primary, recurrent, familial mood disorders and 8 healthy controls using PET and [carbonyl-11 C]WAY-100635. Regions-of-interest (ROI) assessed were the mesiotemporal cortex (hippocampus-amygdala) and midbrain raphe, where previous postmortem studies suggested 5HT1A receptor binding is abnormal in depression. Results: The mean 5HT1A receptor BP was reduced 41.5% in the raphe (p Ͻ .02) and 26.8% in the mesiotemporal cortex (p Ͻ .025) in the depressives relative to the controls.