Mental and somatic comorbidity of depression: a comprehensive cross-sectional analysis of 202 diagnosis groups using German nationwide ambulatory claims data.
抑郁症的精神和躯体共病: 使用德国全国门诊索赔数据对 202 个诊断组进行全面的横断面分析。
- 作者列表："Steffen A","Nübel J","Jacobi F","Bätzing J","Holstiege J
BACKGROUND:Depression is frequently accompanied by other mental disorders and various somatic diseases; however, previous comorbidity studies often relied on self-reported data and have not simultaneously assessed the entire spectrum of mental and somatic diagnoses. The aim is to provide a complete picture of mental and somatic comorbidity of depression in routine outpatient care in a high income country with a relatively well equipped health care system. METHODS:Using ambulatory claims data covering 87% of the German population (age 15+), we designed a cross-sectional study by identifying persons diagnosed with mild, moderate and severe depression in 2017 (N = 6.3 million) and a control group matched 4:1 on sex, 5-year age group and region of residence (N = 25.2 million). Stratified by severity, we calculated the prevalence of 202 diagnosis groups included in the ICD-10 in persons with depression as compared to matched controls using prevalence ratios (PR). RESULTS:Nearly all mental disorders were at least twice as prevalent in persons with depression relative to controls, showing a dose-response relationship with depression severity. Irrespective of severity, the three most prevalent somatic comorbid diagnosis groups were 'other dorsopathies' (M50-M54), 'hypertensive diseases' (I10-I15) and 'metabolic disorders' (E70-E90), exhibiting PRs in moderate depression of 1.56, 1.23 and 1.33, respectively. Strong associations were revealed with diseases of the central nervous system (i.e. multiple sclerosis) and several neurological diseases, among them sleep disorders, migraine and epilepsy, most of them exhibiting at least 2- to 3-fold higher prevalences in depression relative to controls. Utilization of health care was higher among depression cases compared to controls. CONCLUSIONS:The present study based on data from nearly the complete adolescent and adult population in Germany comprehensively illustrates the comorbidity status of persons diagnosed with depression as coded in routine health care. Our study should contribute to increasing the awareness of the strong interconnection of depression with all other mental and the vast majority of somatic diseases. Our findings underscore clinical and health-economic relevance and the necessity of systematically addressing the high comorbidity of depression and somatic as well as other mental diseases through prevention, early identification and adequate management of depressive symptoms.
背景: 抑郁症常伴有其他精神障碍和各种躯体疾病; 然而,以前的共病研究往往依赖于自我报告的数据，没有同时评估精神和躯体诊断的全部范围。目的是在一个设备相对完善的医疗保健系统的高收入国家，在常规门诊护理中提供抑郁症心理和躯体共病的全貌。 方法: 利用覆盖 87% 德国人群 (15 岁以上) 的门诊索赔数据，我们设计了一项横断面研究，通过识别被诊断为轻度、 2017年中度和重度抑郁 (n = 630万)，对照组在性别、 5 岁年龄组和居住地区方面与 4:1 相匹配 (n = 2520万)。按严重程度分层，我们使用患病率比 (PR) 计算了 ICD-10 抑郁症患者中包括的 202 个诊断组与匹配对照者的患病率。 结果: 几乎所有精神障碍在抑郁症患者中的患病率至少是对照组的两倍，显示出与抑郁症严重程度的剂量-反应关系。无论严重程度如何，三个最常见的躯体共病诊断组是 “其他躯体疾病” (M50-M54) 、 “高血压疾病” (I10-I15) 和 “代谢障碍” (E70-E90)，中度抑郁的 PRs 为 1.56,分别为 1.23 和 1.33。与中枢神经系统疾病 (多发性硬化症) 和几种神经系统疾病，其中包括睡眠障碍、偏头痛和癫痫，他们中的大多数表现出抑郁症相对于对照组的患病率至少高 2 至 3 倍。与对照组相比，抑郁症病例的卫生保健利用率较高。 结论: 本研究基于德国几乎完整的青少年和成年人群的数据，全面说明了常规卫生保健中编码的抑郁症患者的共病状况。我们的研究应该有助于提高对抑郁症与所有其他精神和绝大多数躯体疾病的强烈联系的认识。我们的研究结果强调了临床和健康-经济相关性，以及通过预防、早期识别和充分管理抑郁症状来系统解决抑郁症和躯体以及其他精神疾病的高共病的必要性。
METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.