[11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging
Lack 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 binding.
This study aims to assess the antidepressant binding in brain regions of depressed nonresponders compared with healthy controls.
Materials and methods
Healthy 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 2 months 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.
Binding 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.
PET neuroimaging with [11C]mirtazapine showed aberrant neuroreceptor binding in brain regions of depressed subjects who had failed to benefit from treatment with antidepressant drugs.
Get notified about updates to this publicationFollow publication
Click to see the full-text of:
Article: [11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging
- SourceAvailable from: Donald F Smith
[Show abstract] [Hide abstract] ABSTRACT: The search for potential biomarkers of psychiatric disorders is a central topic in biological psychiatry. This review concerns published studies on potential biomarkers of treatment-resistant depression (TRD). The search for biomarkers of TRD in the bloodstream has focused on cytokines and steroids as well as brain-derived neurotropic factor. Additional approaches to identifying biomarkers of TRD have dealt with cerebrospinal fluid analysis, magnetic resonance imaging, and positron emission tomography. Some studies have also investigated potential genetic and epigenetic factors in TRD. Most studies have, however, used a post hoc experimental design that failed to determine the association between biomarkers and the initial risk of TRD. Particular attention in future studies should be on shifting the experimental paradigm toward procedures that can determine the risk for developing treatment resistance in untreated depressed individuals.
- "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. "
[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.
- "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. "
Article: PET neuroimaging in pigs[Show abstract] [Hide abstract] ABSTRACT: Current interest in studying molecular processes as they occur in the living brain has accelerated the use of laboratory animals for neuroimaging of novel radiolabelled compounds. In particular, positron emission tomography (PET) has contributed to the development of radiolabelled compounds for assessing molecular processes in the living brain. The dynamics of PET typically require a relatively large organ size and blood supply in order to properly evaluate radioligand binding kinetics. To fulfil these requirements, pigs have often been used in such studies. Today, much is known about the metabolism, neurotransmission and molecular binding properties of the living porcine brain, and most findings support similarities between neuronal mechanisms in pigs and humans. Here, we review 10-years of PET findings on neuromolecular processes in the living porcine brain and, whenever possible, we relate PET findings in pigs to those obtained in humans.