[11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging

Psychopharmacology (Impact Factor: 3.88). 09/2009; 206(1):133-140. DOI: 10.1007/s00213-009-1587-3


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.

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Available from: Poul Videbech, Jul 22, 2015
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    • "Brain imaging by positron emission tomography (PET) has often been used to study potential biomarkers of depressive disorders as well as to investigate potential beneficial effects of antidepressant drugs (Mayberg et al., 2000; Mayberg, 2007; Hoflich et al., 2012), but PET has rarely been used specifically for studying TRD. Thus, Smith et al. (2009) used the traditional post hoc design in their PET study of mirtazapine binding in brain regions of subjects with well-established TRD and healthy subjects. They found moderately reduced binding of radiolabeled mirtazapine in regions of the cerebral cortex and basal ganglia of TRD subjects compared with healthy subjects. "
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    • "Central actions of psychotropic drugs continue to be of interest in PET brain imaging [22-24]. Our work shows that mirtazapine, an effective antidepressant drug, has favorable properties for PET brain imaging when the compound is radiolabeled with 11C in the N-methyl position [10,25,26]. As far as we know, [N-methyl-11C]mirtazapine is the only radioligand of a popular antidepressant drug that is suitable for PET imaging of the brain in humans. "
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    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.
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