Striatal Dopamine D₂ Receptors Changes In Patients Of First-episode Major Depressive Disorder And Correlation Analysis Of Clinical Features

Background and purposeMajor depressive disorder is a kind of mood disorders or emotional disorders caused by various factors, and depression is the main clinical manifestation. Patients feel low as the main symptom, accompanied by pessimism and despair, as well as serious suicidal tendenciy. The incidence rate of major depressive disorder is as high as 3% to 16.9%, and it has become the disease of world’s fourth largest medical burden, causing great impact on social stability and economic development. As a result, countries around the world attach great importance to major depressive disorder, and a large number of researches were carried out on its pathogenesis and clinical treatment. However, because of the complexity of the disease itself, its biological mechanism has not been fully illuminated. Traditionally major depressive disorder is thought to be associated with dysfunction of monoamine neurotransmitters system in the brain and decrease of monoamine neurotransmitters leads to depression, namely the central monoamine neurotransmitter dysfunction hypothesis. Monoamine neurotransmitter theory plays a leading role in the pathogenesis of major depressive disorder, and affects the development and application of antidepressants. But it is difficult for this hypothesis to explain the contradiction that antidepressant drugs cause the body neurotransmitter concentrations to change quickly, but it takes a long period of time to have treatment effects. Neurotransmitters in the brain must combine with the corresponding specific receptors to play a role. Then the researchers focused on receptors and thought that the abnormalities of neurotransmitters caused the dysfunction of corresponding receptors, leading to the onset of major depressive disorder, namely brain receptor hypothesis.The abnormality of reward circuit in the mesolimbic dopamine system is closely related to the pathogenesis of major depressive disorder. And among the five kinds of dopamine receptors, dopamine D₂ receptor is mainly distributed in the mesolimbic system.Therefore the abnormality of dopamine D₂ receptor is closely related to major depressive disorder. There are a lot of researches about dopamine D₂ receptor with major depressive disorder abroad, but part of the results are consistency and part are contradictory because of different subjects and methods. Thus it is difficult to explain the role of dopamine D₂ receptor in the etiology and pathogenesis of major depressive disorder. ¹¹C-raclopride is the most widely-used positron radioligand for dopamine D₂ receptor. This research studied a group of patients with first-episode major depressive disorder with the ¹¹C-raclopride positron emission tomography（PET）/computed tomography（CT） scanning, ruling out confounding factors such as medication and smoking of the patients, to observe striatal dopamine D₂ receptor changes and combined with Hamilton depression rating scale（HAMD） to make correlation analysis. The striatal dopamine D₂ receptor changes and the relationship between striatal dopamine D₂ receptor changes and patients’ behavior changes will be discussed. We hope that the research will be benefit on the etiology, pathogenesis and clinical diagnosis and treatment of major depressive disorder. Materials and methodsSubjects: MDD patients were collected from December 2014 to December 2015 at the People’s Hospital of Zhengzhou University, Department of Neurology. The control group included healthy volunteers. All subjects met the inclusion criteria and exclusion criteria. 20 MDD patients and 20 healthy controls who matched with MDD patients in age and gender were included to data analysis.Examination method: 3D T1 fast spoiled gradient recalled（FSPGR） MRI scan was conducted 1³ days before brain ¹¹C-raclopride PET/CT examination by U.S. GE Discovery 750 MR scanner. All the scan time were fixed at 3:00 pm⁶:00 pm. And all subjects were asked to have a rest for 30 minutes in a quiet room before scanning and they were required to wear eye shields and keep awake, and their heads were fixed during the examination. Imaging device of ¹¹C-raclopride PET/CT examination was U.S. GE DiscoveryTM VCT PET/CT scanner. Firstly CT collection was conducted, and then PET acquisition was carried out. CT data was used to make attenuation correction of PET images. CT parameters were set to 120 k V voltage, 240 m A current, thickness 3.75 mm. PET collection was applied with 3D, dynamic scanning and volume imaging protocol（VIP） reconstruction model, and every subject was given ¹¹C-Raclopride 111²70MBq intravenously. PET collection was set to 15s/frame×20, 60s/frame×25, 180s/frame×10, and total acquisition time was 1 h.Data processing: Molecular imaging and kinetic analysis toolbox（MIAKAT） based on MATLAB was used to process dynamic PET data and 3D T1 data, and non-displaceable binding potential（BPND） was calculated on the basis of simplified reference tissue model（SRTM）. Steps in detail: a.brain extraction; b.brain tissue segmentation; c.motion correction; d.ROI tracer kinetic modelling; e.parametric imaging. Brain parametric imagings, time-activity curves and BPND values of each subject were obtained through the comprehensive of model technology.Statistical analysis: Bilateral striatal（caudate nucleus and putamen） dopamine D₂ receptor BPND within the patient group and control group were compared, and ipsilateral striatal（caudate nucleus and putamen） dopamine D₂ receptor BPND between the patient group and control group were compared, respectively, using SPSS20.0 software to make two independent samples t-test（p<0.05）; The correlation analysis between bilateral striatal dopamine D₂ receptor BPND and behavioral changes of the patient group were conducted by SPSS20.0 software, and bilateral striatal dopamine D₂ receptor BPND and the total score and 7 kinds of factor scores of depression were made Pearson correlation analysis respectively（p<0.05）. Results1. The result of bilateral striatal D₂ receptor BPND within the MDD group and control groupThe bilateral striatal D₂ receptor BPND of the MDD group had no statistical differences; and the bilateral striatal dopamine D₂ receptors BPND of the control group had no statistical differences, too.2. The result of ipsilateral striatal D₂ receptors BPND between MDD and controlsCompared with the control group, the bilateral striatal（caudate nucleus and putamen） D₂ receptor BPND of the MDD group all showed reduction.3. The result of correlation analysis between bilateral striatal D₂ receptor BPND and the total scores and 7 kinds of factor scores of HAMD of the MDD groupThe total scores of HAMD of the MDD group were negatively correlated with BPND of bilateral caudate nucleus and putamen respectively; the scores of anxiety/somatization showed negative relationship with BPND of the bilateral caudate nucleus and putamen respectively; the scores of cognitive impairment were negatively correlated with BPND of bilateral caudate nucleus and left putamen respectively; the scores of retardation showed negative relationship with BPND of the bilateral caudate nucleus; and the scores of sleep disturbance showed negative relationship with BPND of the left caudate nucleus.Conclusion1. Bilateral striatal dopamine D₂ receptors BPND of MDD showed reduction, which implied the dopamine D₂ receptors function and dopamine system function of MDD decline.2. The reduction of bilateral striatal dopamine D₂ receptors BPND were closely related with various symptoms of MDD confirmed that the abnormality of dopamine D₂ receptors played an important role in the pathogenesis of MDD, which supported the hypothesis that brain receptors abnormality was existed in MDD.3. The abnormality of striatal dopamine D₂ receptors may be one of the important molecular mechanisms of the midbrain-striatal dopamine reward circuits of MDD.