[11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging
ABSTRACT RationaleLack of benefit from antidepressant drug therapy is a major source of human suffering, affecting at least 25% of people with
major depressive disorder. We want to know whether nonresponse to antidepressants can be linked to aberrant neuroreceptor
ObjectiveThis study aims to assess the antidepressant binding in brain regions of depressed nonresponders compared with healthy controls.
Materials and methodsHealthy volunteers and depressed subjects who had failed to benefit from at least 2 antidepressant treatments were recruited
by newspaper advertisements. All subjects had received no antidepressant medication for at least 2months before positron
emission tomography (PET) that was carried out with [11C]mirtazapine. Kinetic parameters of [11C]mirtazapine were determined from PET data in selected brain regions by the simplified reference tissue model.
ResultsBinding potentials of [11C]mirtazapine in cerebral cortical regions were lower in depressed nonresponders than in healthy controls. Removal rates of
[11C]mirtazapine were higher in diencephalic regions of depressed nonresponders than in healthy controls.
ConclusionsPET neuroimaging with [11C]mirtazapine showed aberrant neuroreceptor binding in brain regions of depressed subjects who had failed to benefit from
treatment with antidepressant drugs.
- SourceAvailable from: Donald F Smith[Show abstract] [Hide abstract]
ABSTRACT: We compared six kinetic models with and without the requirement of arterial cannulation for estimating the binding potential of [N-methyl-11C]mirtazapine in the living human brain. Distribution volumes of [N-methyl-11C]mirtazapine in brain regions were estimated using single- and two-tissue compartment models as well as a graphical plasma input model. The two-tissue compartment model provided a direct estimate of the binding potentials of [N-methyl-11C]mirtazapine in brain regions, while binding potentials of the single-tissue compartment model and the graphical plasma input model were estimated indirectly from ratios of distribution volumes in brain regions. We obtained also direct estimates of binding potentials using a graphical reference tissue model and two nonlinear reference tissue models. The two-tissue compartment model required several fits with different initial guesses for avoiding negative values of parameters. Despite the extra fits, estimates of distribution volumes and binding potentials of [N-methyl-11C]mirtazapine obtained by the two-tissue compartment model were far more variable than those produced by the other methods. The graphical plasma input method and the graphical reference tissue method provided estimates of the binding potential that correlated closely, but differed in magnitude. The single-tissue compartment model provided relatively low estimates of binding potentials with curves that failed to fit the data as well as the three other methods that used the entire series of positron emission tomography data. The reference tissue method and the simplified reference tissue method provided similar, consistent estimates of binding potentials. However, certain assumptions of the simplified reference tissue method may not be fulfilled by the radioligand. The reference tissue method is appropriate for estimating the binding potential of [N-methyl-11C]mirtazapine in regions of the human brain so that the binding potential of [N-methyl-11C]mirtazapine can be estimated without arterial cannulation.12/2011; 1(1):36. DOI:10.1186/2191-219X-1-36
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ABSTRACT: In the present study, we evaluated the contribution of the individual synaptic constituents of all assessed neurotransmitter systems by subjecting all available in vivo imaging studies on patients with unipolar major depressive disorder (MDD) and bipolar depression (BD) to a retrospective analysis. In acute MDD, findings revealed significant increases of prefrontal and frontal DA synthesis, decreases of thalamic and midbrain SERT, increases of insular SERT, decreases of midbrain 5-HT(1A) receptors and decreases of prefrontal, frontal, occipital and cingulate 5-HT(2A) receptors, whereas, in remission, decreases of striatal D₂ receptors, midbrain SERT, frontal, parietal, temporal, occipital and cingulate 5-HT(1A) receptors and parietal 5-HT(2A) receptors were observed. In BD, findings indicated a trend towards increased striatal D₂ receptors in depression and mania, decreased striatal DA synthesis in remission and decreased frontal D₁ receptors in all three conditions. Additionally, there is some evidence that ventrostriatal and hippocampal SERT may be decreased in depression, whereas in remission and mania elevations of thalamic and midbrain SERT, respectively, were observed. Moreover, in depression, limbic 5-HT(1A) receptors were elevated, whereas in mania a decrease of both cortical and limbic 5-HT(2A) receptor binding was observed. Furthermore, in depression, prefrontal, frontal, occipital and cingulate M2 receptor binding was found to be reduced. From this, a complex pattern of dysregulations within and between neurotransmitter systems may be derived, which is likely to be causally linked not only with the subtype and duration of disease but also with the predominance of individual symptoms and with the kind and duration of pharmacological treatment(s).Behavioural brain research 03/2012; 232(2):358-90. DOI:10.1016/j.bbr.2012.03.021 · 3.39 Impact Factor
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ABSTRACT: 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.Frontiers in Psychiatry 03/2013; 4:8. DOI:10.3389/fpsyt.2013.00008