5-羟色胺和胆固醇水平对抑郁症患者再次自杀风险评估的研究

目的 探讨抑郁症患者血小板5-羟色胺（5-HT）和胆固醇水平与抑郁症患者再次自杀的关系.方法 对33例有自杀行为的抑郁症患者在接受治疗前测定血小板5-HT和胆固醇水平,评定汉密尔顿抑郁量表（HAMD-24）和Beck绝望量表（BHS）,然后进行2年的随访.结果 16例患者再次出现自杀行为,再次自杀组血小板5-HT及血清胆固醇水平显著低于无再次自杀组（P＜0.01）.5-HT和血清胆固醇水平与HAMD-24、BHS分及自杀次数、自杀严重程度均呈负相关（P＜0.01）,且5-HT与血清胆固醇水平呈正相关（P＜0.01）.多重回归分析显示血小板5-HT浓度、家族史是自杀次数的主要影响因素.结论 低血小板5-HT及血清胆固醇浓度是抑郁症自杀的危险因素,对抑郁症自杀行为可能具有一定的的预测作用.     

Serotonin transporter binding as a possible predictor of one-year remission in major depressive disorder

Objective

Lower serotonin transporter (5-HTT) binding (BP_P = f_PB_avail/K_D) is reported during a major depressive episode (MDE) compared to healthy controls. Higher 5-HTT binding in the diencephalon has previously been associated with acute response to antidepressant treatment. We assessed baseline 5-HTT binding as a predictor of one-year remission from a MDE, examining binding in brain regions implicated in the pathophysiology of major depressive disorder (MDD).

Methods

5-HTT binding was quantified using positron emission tomography (PET) with [¹¹C]McN5652 in 19 currently depressed subjects with MDD and 41 healthy controls. Depressed subjects received open, naturalistic antidepressant treatment. Remission status was determined one year after PET scan and treatment initiation.

Results

Significant differences in 5-HTT binding among the three groups (healthy controls, remitters, and non-remitters) were observed in a linear mixed-effects model. Post hoc, non-remitters had lower 5-HTT binding than controls in midbrain, amygdala, and anterior cingulate. Remitters did not differ significantly from controls or non-remitters in 5-HTT binding. Remitters did not differ from non-remitters in clinical characteristics apart from greater family history of depression among non-remitters. A logistic regression model fit to determine the capacity of baseline 5-HTT binding to predict remission status at one year yielded a coefficient that was suggestive but not significant (p = 0.057).

Limitations

The small sample size and heterogeneous treatments received reduced statistical power to detect differences in binding based on clinical outcome.

Conclusions

Lower pretreatment 5-HTT binding may be predictive of non-remission from major depression following one year of naturalistic antidepressant treatment. Future studies using standardized treatment are warranted.     

5-羟色胺基因多态性与抑郁症的相关性研究

目的：探讨5-羟色胺转运体(5-HTT)基因启动子区多态性(5-HTTLPR)与抑郁症的相关性及其对抗抑郁药疗效的影响。方法：运用聚合酶链反应技术(PCR)检测51例抑郁症患者(患者组)和60名健康对照者(对照组)5-HTTLPR的分布频率；并予文拉法辛治疗，用汉密尔顿抑郁量表(HAMD)观察疗效。结果：患者组5-HTTLPR的短重复序列／短重复序列(short／short，S／S)基因型和短重复序列(short，S)等位基因频率分别为71％和81％，对照组为45％和69％差异显著。治疗4周后，长重复序列／长重复序列(long／long，L／L)基因型患者的减分率显著高于其他两型。结论：5-HTTLPR的S／S基因型可能是抑郁症的易感基因之一，L／L基因型可能和更好的选择性5-羟色胺受体阻滞剂类(SSRIs)疗效有关。     

Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Standard therapeutic interventions are aimed at replenishment of empty dopamine stores with levodopa or substitution with dopamine receptor agonists. However, in the long term this symptomatic therapy fails. Currently, various neuroprotective agents are being developed, with the intention to slow down the degeneration of dopaminergic neurons. In this context, the early identification of persons at risk to develop the disease as well as the assessment of the effectiveness of putative neuroprotective agents, are critical issues. Dopamine transporter (DAT) scintigraphy with single photon emission computed tomography (SPECT) has been used to assess the dopaminergic function in PD. Initial studies with several radioligands show significant loss of DAT binding in PD patients as compared to controls. In this paper we review the evidence on the utility of DAT imaging with SPECT in early PD detection as well as in monitoring neurprotection.     

Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress

Accumulated evidence indicates a role of the hippocampal 5-hydroxy-tryptamine (5-HT) and neuropeptide Y (NPY) in the response to stress and modulation of depression, but it is unclear whether and how the hippocampal 5-HT and NPY systems make contributions to chronic unpredicted mild stress (CUMS)-induced depression. Here we observed that rats receiving a variety of chronic unpredictable mild stressors for 3 weeks showed a variety of depression-like behavioral changes, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test. These CUMS-induced behavioral changes were suppressed or blocked by intra-hippocampal injection of 5-HT (31.25 μg/μl) or NPY (10 μg/μl). These data suggest a critical role of reduced hippocampal 5-HT and NPY neurotransmission in CUMS-induced depression.     

Pet imaging studies of dopamine D2 receptors: Comparison of [18F]N-Methylspiperone; and the benzamide analogues [18F]MABN and [18F]MBP in baboon brain

A series of positron emission tomography (PET) imaging studies was conducted in a baboon with the benzamide derivatives [¹⁸F]2,3-dimethoxy N-9-(4-fluorobenzyl)-9-azabicyclo[3.3.1]nonan-3β-yl]benzamide ([¹⁸F]MABN) and [¹⁸F]2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin-4-yl]benzamide ([¹⁸F]MBP). Studies were also conducted with the butyrophenone [¹⁸F]N-methylspiperone (NMSP) for comparison. Tissue-time activity curves of [¹⁸F]MABN are similar to those of [¹⁸F]NMSP since both compounds displayed approximately the same uptake in the basal ganglia and displayed irreversible binding kinetics in vivo. However, the rapid rate of clearance from the cerebellum and high basal ganglia: cerebellum ratio of [¹⁸F]MABN indicate that this compound has a much lower amount of nonspecific binding than [¹⁸F]NMSP. [¹⁸F]MBP displayed a higher uptake in the basal ganglia relative to [¹⁸F]NMSP and [¹⁸F]MABN and exhibited reversible binding kinetics in vivo. This property of [¹⁸F]MBP is desirable since the uptake of radioactivity in D₂-rich ligands is less likely to be influenced by changes in cerebral blood flow. The current data suggest that both [¹⁸F]MABN and [¹⁸F]MBP are promising ligands for studying dopamine D₂ receptors with PET. © 1995 Wiley-Liss, Inc.     

The 5-HT2A receptor and serotonin transporter in Asperger's Disorder: A PET study with [C]MDL 100907 and [C]DASB

Evidence from biochemical, imaging, and treatment studies suggest abnormalities of the serotonin system in autism spectrum disorders, in particular in frontolimbic areas of the brain. We used the radiotracers [¹¹C]MDL 100907 and [¹¹C]DASB to characterize the 5-HT_2A receptor and serotonin transporter in Asperger's Disorder. Seventeen individuals with Asperger's Disorder (age = 34.3 ± 11.1 years) and 17 healthy controls (age = 33.0 ± 9.6 years) were scanned with [¹¹C]MDL 100907. Of the 17 patients, eight (age = 29.7 ± 7.0 years) were also scanned with [¹¹C]DASB, as were eight healthy controls (age = 28.7 ± 7.0 years). Patients with Asperger's Disorder and healthy control subjects were matched for age, gender, and ethnicity, and all had normal intelligence. Metabolite-corrected arterial plasma inputs were collected and data analyzed by two-tissue compartment modeling. The primary outcome measure was regional binding potential BP_ND. Neither regional [¹¹C]MDL 100907 BP_ND nor [¹¹C]DASB BP_ND was statistically different between the Asperger's and healthy subjects. This study failed to find significant alterations in binding parameters of 5-HT_2A receptors and serotonin transporters in adult subjects with Asperger's Disorder.     

Subdural engraftment of serotonergic neurons following spinal hemisection restores spinal serotonin, downregulates serotonin transporter, and increases BDNF tissue content in rat

Spinal hemisection injury at T13 results in development of permanent mechanical allodynia and thermal hyperalgesia due to interruption and subsequent loss of descending inhibitory modulators such as serotonin (5-HT) and its transporter (5-HT(T)). We hypothesize that lumbar transplantation of non-mitotic cells that tonically secrete 5-HT and brain-derived neurotrophic factor (BDNF) will restore alterations in 5-HT and 5-HT(T) systems within the spinal dorsal horn. We used an immortalized rat neuronal cell line derived from E13 raphe (RN46A-B14) which is shown to secrete 5-HT and BDNF in vitro and in vivo. Three groups (n=35) of 30 day old male Sprague-Dawley rats were spinally hemisected at T13 and 28 days later received either lumbar RN46A-V1 control empty-vector (n=15) or RN46A-B14 (n=15) intrathecal grafts, or no transplant. Twenty-eight days following transplantation, animals were perfused and tissue examined for changes in 5-HT, 5-HT(T), and BDNF at the site of transplantation or at lumbar enlargements (L5). Immunohistochemistry revealed that RN46A-B14, but not RN46A-V1 cells, increased 5-HT tissue staining at L5 in the dorsal white matter as well as in superficial dorsal horn laminae I and II on both ipsilateral and contralateral sides, results confirmed by ELISA. Transplantation of RN46A-B14 cells significantly reduced ipsilateral 5-HT(T), upregulated after injury. Significantly increased levels of BDNF were also observed after RN46A-B14 transplantation but were not localized to particular spinal laminae. These results are consistent with recovery of locomotor function and reductions in chronic pain behaviors observed behaviorally after RN46A-B14 transplantation and supports the pragmatic application of cell-based therapies in correcting damaged circuitry after spinal cord injury.     

Circadian regulation of depression: A role for serotonin

Synchronizing circadian (24 h) rhythms in physiology and behavior with the environmental light-dark cycle is critical for maintaining optimal health. Dysregulation of the circadian system increases susceptibility to numerous pathological conditions including major depressive disorder. Stress is a common etiological factor in the development of depression and the circadian system is highly interconnected to stress-sensitive neurotransmitter systems such as the serotonin (5-hydroxytryptamine, 5-HT) system. Thus, here we propose that stress-induced perturbation of the 5-HT system disrupts circadian processes and increases susceptibility to depression. In this review, we first provide an overview of the basic components of the circadian system. Next, we discuss evidence that circadian dysfunction is associated with changes in mood in humans and rodent models. Finally, we provide evidence that 5-HT is a critical factor linking dysregulation of the circadian system and mood. Determining how these two systems interact may provide novel therapeutic targets for depression.     

Traumatic brain injury decreases serotonin transporter expression in the rat cerebrum

Objectives: An association has been postulated between traumatic brain injury (TBI) and depression. The serotonin transporter (SERT) regulates the concentration of serotonin in the synaptic cleft and represents a molecular target for antidepressants. We hypothesized that SERT expression in the brain changes following TBI.

Methods: We performed immunohistochemistry, real-time polymerase chain reaction analysis for mRNA and western blot analysis for protein to examine the time-dependent changes in SERT expression in the cerebrum during the first 14 days after TBI, using a controlled cortical impact model in rats.

Results: SERT immunoreactivity in neuronal fibres within the area adjacent to the cortical contusion decreased 1 to 14 days after injury. Significantly decreased SERT mRNA and protein expression were noted in the area adjacent to the cortical contusion 7 days after injury. There were no significant changes in SERT expression in the cingulum of the injured brain.

Discussion: The findings of this study indicate that TBI decreases SERT expression in the cerebral cortex. The decreased levels of SERT expression after TBI may result in decreased serotonin neurotransmission in the brain and indicate a possible relationship with depression following TBI.     

An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [¹⁸F]-setoperone for 5-HT2 binding potential (BP) and [¹¹C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [¹⁸F]-setoperone and with [¹¹C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as ≥50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.     

A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria

The cause of premenstrual dysphoric disorder (PMDD) is largely unknown. It has been hypothesized that normal ovarian function triggers PMDD-related biochemical events within the brain and that serotonin plays an important role. In the present study, positron emission tomography (PET) and [carbonyl-¹¹C]WAY-100635 were used to examine serotonin 5-HT_1A receptors in a control group of women and in a group of women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). Each subject's menstrual cycle was confirmed by ultrasonography of the ovaries as well as with hormone levels in blood and urine. The 5-HT_1A binding potential was measured in six regions of interest and calculated according to the simplified reference tissue model. In the raphe nuclei, the 5-HT_1A binding potential changed from the follicular to the luteal phase of the menstrual cycle in asymptomatic controls. In women with PMDD, the observed change between phases was significantly smaller. The results are in concordance with previously reported challenge studies of 5-HT_1A receptor-mediated effects indicating different serotonergic responses between women with PMDD and controls. The study principally provides new support, in vivo, for a serotonergic dysregulation in women with PMDD.     

Attenuated serotonin transporter association between dorsal raphe and ventral striatum in major depression

Suffering from anhedonia, patients with major depressive disorder (MDD) exhibit alterations in several parts of the serotonergic neurotransmitter system, which are in turn involved in reward processing. However, previous investigations of the serotonin transporter (SERT) focused on regional differences with varying results depending on the clinical syndrome. Here, we aimed to describe the serotonergic system of MDD patients on a network level by evaluating SERT associations across brain regions. Twenty medication free patients with major depression and 20 healthy controls underwent positron emission tomography using the radioligand [¹¹C]DASB. SERT binding potentials (BP_ND) were quantified voxel‐wise with the multilinear reference tissue model 2. In addition, SERT BP_ND was extracted from the dorsal raphe nucleus (DRN) as an indicator of midbrain serotonergic neurotransmission. Whole‐brain linear regression analysis was applied to evaluate the association of DRN SERT bindings to those in projection areas, which was followed by ANCOVA to assess differences in interregional relationships between patients and controls. Although both groups showed widespread positive correlations, group differences were restricted to decreased SERT associations between the DRN and the ventral striatum (right and left respectively: t = 5.85, P < 0.05 corrected and t = 5.07, P < 0.1 corrected) when comparing MDD patients (R² = 0.11 and 0.24) to healthy subjects (R² = 0.72 and 0.66, P < 0.01 and 0.05 corrected). Adjusting for age and sex did not change these findings. This study indicates a disturbed regulation between key regions involved in reward processing via the SERT. Our interregional approach highlights the importance of evaluating pathophysiological alterations on a network level to gain complementary information in addition to regional investigations. Hum Brain Mapp 35:3857–3866, 2014. © 2014 Wiley Periodicals, Inc.     

Kinetics of the uptake of [3H]paroxetine in the rat brain

Paroxetine, an antidepressant with a high affinity for serotonin (5-HT) re-uptake sites, is a potential tracer of these sites. We determined the kinetic properties of [³H]paroxetine in rat brain in vivo. Relative to [¹⁴C]iodo-antipyrine, the brain uptake index (BUI) of [³H]paroxetine was 60–70%. The unidirectional blood clearance of [³H]paroxetine were 0.05–0.12 ml g^?1 min^?1, lower than expected from the BUI values. The steady state volume of distribution was 3.5 ml hg^?1 in the diencephalon and 1.8 ml ^?1 in the cerebellum, suggesting a binding potential of unity. Autoradiographs at four hours after [³H] paroxetine injection (300 μCi, i.p.) revealed heterogenous binding consistent with the calculated binding potentials. Binding was nearly absent from cerebellum and was highest in the dorsal raphé, superior colliculus, dorsal hypothalamus, and entorhinal cortex, but did not reach equilibrium in four hours of tracer circulation. The specific binding relative to vermis was displaced by pretreatment with fluonotino (10 mg/kg, i.p.). © 1993 Wiley-Liss. Inc.     

Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: A preliminary report

We evaluated positron emission tomography (PET) in the differential diagnosis of depression and Alzheimer's disease. The local cerebral metabolic rate for glucose (LCMRGlc) in the parahippocampal gyrus-hippocampus and the dorsolateral prefrontal cortex were determined. The ratio of the LCMRGlc in those two regions was examined in patients with unipolar depression, bipolar depression, and Alzheimer's dementia. An analysis of variance revealed significant overall intergroup differences in values for both hemispheres. Student's t test showed significant differences in LCMRGlc for both unipolar and bipolar depression as compared with Alzheimer's dementia. These data indicate that PET may be useful in the differential diagnosis of dementia vs. depression.     

Olfactory function in psychotic disorders: Insights from neuroimaging studies

Olfactory deficits on measures of identification, familiarity, and memory are consistently noted in patients with psychotic disorders relative to age-matched controls. Olfactory intensity ratings, however, appear to remain intact while the data on hedonics and detection threshold are inconsistent. Despite the behavioral abnormalities noted, no specific regional brain hypoactivity has been identified in psychosis patients, for any of the olfactory domains. However, an intriguing finding emerged from this review in that the amygdala and pirifom cortices were not noted to be abnormal in hedonic processing (nor was the amygdala identified abnormal in any study) in psychotic disorders. This finding is in contrast to the literature in healthy individuals, in that this brain region is strongly implicated in olfactory processing (particularly for unpleasant odorants). Secondary olfactory cortex (orbitofrontal cortices, thalamus, and insula) was abnormally activated in the studies examined, particularly for hedonic processing. Further research, using consistent methodology, is required for better understanding the neurobiology of olfactory deficits. The authors suggest taking age and sex differences into consideration and further contrasting olfactory subgroups (impaired vs intact) to better our understanding of the heterogeneity of psychotic disorders.     

Serotonin transporter availability in impulsive aggressive personality disordered patients: A PET study with [11C]DASB

Serotonin (5-HT) has consistently been implicated in the pathophysiology of impulsive aggression. In the current study, we tested the hypothesis that 5-HT transporter (5-HTT) binding is reduced in the anterior cingulate cortex (ACC) in impulsive aggressive patients. Additionally, we characterized pathological personality dimensions, with a specific focus on callousness (i.e. emotional indifference, a facet of psychopathy). Callousness is putatively positively correlated with presynaptic 5-HT, and thus could potentially confound the hypothesized negative relation between 5-HTT levels and trait aggression.We determined 5-HTT binding with positron emission tomography and [¹¹C]DASB in 29 patients with intermittent explosive disorder (IED-IR) and 30 controls. We assessed group differences in 5-HTT binding in the pregenual ACC, amygdala and subcortical regions and examined correlations between 5-HTT binding and clinical measures.There were no significant differences in 5-HTT binding between IED-IR patients and controls. Trait callousness exhibited a significant, positive correlation with ACC 5-HTT availability. Among IED-IR patients, a trend-level negative partial correlation was observed between trait aggression and ACC 5-HTT availability, while covarying for callousness and age. Exploratory analyses revealed a significant negative correlation between state aggression levels and 5-HTT availability in subcortical regions, namely striatum and thalamus.We did not confirm our hypothesis of lower ACC 5-HTT availability in impulsive aggressive patients, however, the positive correlation between callousness and ACC 5-HTT availability likely played a confounding role. Subtypes of aggression (e.g., reactive vs. proactive aggression), which are differentially associated with pathological personality dimensions such as callousness, may contribute to variability between 5-HT functioning and aggression.