Molecular imaging of depressive disorders

This chapter summarizes findings of a large number of molecular imaging studies in the field of unipolar and bipolar depression (BD). Brain metabolism in depressed unipolar and bipolar patients is generally hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Interestingly, after depletion of serotonin or noradrenalin/dopamine in vulnerable (recovered) major depressive disorder (MDD) patients, a similar response pattern in metabolism occurs. Findings on the pre- and postsynaptic dopaminergic system show indications that, at least in subgroups of retarded MDD patients, presynaptic dopaminergic markers may be decreased, while postsynaptic markers may be increased. The findings regarding serotonin synthesis, pre- and postsynaptic imaging can be integrated to a presumable loss of serotonin in MDD, while this remains unclear in BD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. This should be addressed further in future studies. Furthermore, future longitudinal molecular imaging studies in the same subjects at different clinical mood states are needed to clarify whether the observed changes in transporters and receptors are compensatory reactions or reflect different, potentially causal mechanisms. Several suggestions for future developments are also provided.</p

Chronic stress and antidepressant treatment have opposite effects on P-glycoprotein at the blood–brain barrier: an experimental PET study in rats

The multi-drug efflux transporter P-glycoprotein is expressed in high concentrations at the blood–brain barrier and has a major function in the transport of drugs. In a recent PET-study evidence was found for an increased function of P-glycoprotein at the blood–brain barrier in medicated patients suffering from major depressive disorder. We used small-animal PET and [11C]-verapamil to study P-glycoprotein function at the blood–brain barrier of rats, either being administered as venlafaxine, an antidepressant, or subjected to chronic stress, a factor contributing to the development of depression. In a first experiment, male Wistar rats underwent a three-week foot shock procedure as a model of human depression. In a second experiment, rats were chronically treated with the antidepressant venlafaxine (25 mg/kg/d via an implanted osmotic minipump). In both experiments, a [11C]-verapamil PET scan was performed. In the chronically stressed rats, the distribution volume (VT) of [11C]-verapamil was significantly increased, whereas treatment with venlafaxine had the opposite effect and caused a significant reduction in VT. The changes in VT could not be attributed to the influx rate constant (K1). Our data suggest that P-glycoprotein function at the blood–brain barrier is inhibited by chronic stress and increased by chronic administration of venlafaxine.