Depressionen und Lebererkrankungen: Die Rolle von Mikrobiom und Inflammation

Zusammenfassung

Zwischen Depressionen und Lebererkrankungen besteht ein e nger Zusammenhang. Jeder dritte Leberzirrhosepatient und jeder dritte Hepatitispatient ist depressiv. Andererseits entwickelt jeder dritte Patient mit Depressionen im Verlauf seines Lebens eine Alkoholerkrankung, in deren Folge Lebererkrankungen auftreten können. Ein entscheidendes Bindeglied zwischen Lebererkrankungen und Depressionen sind Entzündungsprozesse. Das systemische inflammatorische Milieu ist bei vielen Lebererkrankungen verändert. Außerdem scheint das Mikrobiom und eine erhöhte intestinale Permeabilität des Darms eine große Bedeutung zu haben. Sowohl Depressionen als auch Lebererkrankungen, Alkoholkonsum, Stress und Altersprozesse verschieben das empfindliche Gleichgewicht der Darmmikrobiota und resultieren in einer erhöhten intestinalen Permeabilität. Bakterien und ihre Metabolite wie das Endotoxin Lipopolysaccharid können so in die Blutzirkulation gelangen und sowohl in der Leber als auch im Gehirn über eine Zytokinkaskade Entzündungen auslösen, die wiederum zu Leberveränderungen sowie zu Depressionen, Adipositas und metabolischem Syndrom führen. Daher sollten bei depressiven Erkrankungen Leberentzündungswerte wie auch Marker für die Lebersynthese und Leberentgiftungsfunktion regelmäßig kontrolliert werden. Umgekehrt sollte bei Patienten mit Lebererkrankungen verstärkt auf depressive Symptome geachtet werden, die eine differentielle Therapie unter Berücksichtigung des Stadiums der Lebererkrankung erfordern.

Abstract

Depression and liver disease are closely associated. Every third patient with liver cirrhosis or hepatitis shows depressive symptoms. On the other hand, every third patient with depressive disorder develops an alcohol disorder at some point during his / her life. A crucial link between depression and hepatic disease seems to be inflammatory processes in which the microbiome and increased intestinal permeability of the intestine play a pivotal role. Depression as well as liver disease, alcohol consumption, stress, and aging processes disturb the delicate balance of intestinal microbiota resulting in increased intestinal permeability. Therefore, bacteria or their metabolites such as the endotoxine lipopolysaccharide are able to reach the blood circulation resulting in inflammation in the liver as well as in the brain via a cytokine cascade, which in turn can lead to liver changes, depression, obesity, and metabolic syndrome. Therefore, liver values, blood glucose levels, and metabolic parameters should be closely monitored in patients with depressive disorders, and in the case of patients with hepatic diseases, increased attention should be given to depressive symptoms, diabetes and obesity.

Schlüsselwörter

Depression - Lebererkrankung - Mikrobiom - Inflammation

Key words

major depressive disorder - liver disease - microbiome - inflammation

• Literatur

• 1 Bianchi G, Marchesini G, Nicolino F. et al. Psychological status and depression in patients with liver cirrhosis. Dig Liver Dis 2005; 37: 593-600
• 2 Zhu HP, Gu YR, Zhang GL. et al. Depression in patients with chronic hepatitis B and cirrhosis is closely associated with the severity of liver cirrhosis. Exp Ther Med 2016; 12: 405-409
• 3 Fortier E, Alavi M, Bruneau J. et al. Depression, Anxiety, and Stress Among People With Chronic Hepatitis C Virus Infection and a History of Injecting Drug Use in New South Wales, Australia. J Addict Med 2017; 11: 10-18
• 4 Deterding K, Gruner N, Buggisch P. et al. Symptoms of anxiety and depression are frequent in patients with acute hepatitis C and are not associated with disease severity. Eur J Gastroenterol Hepatol 2016; 28: 187-192
• 5 Golden J, O’Dwyer AM, Conroy RM. Depression and anxiety in patients with hepatitis C: prevalence, detection rates and risk factors. Gen Hosp Psychiatry 2005; 27: 431-438
• 6 Baeg JY, Kim IH, Seo SY. et al. Prevalence and Incidence of Depression during Interferon-Based Antiviral Therapy in Chronic Hepatitis C Patients in the Republic of Korea. Gut liver 2017; , DOI: DOI: 10.5009/gnl16242.
• 7 Rogal SS, Mankaney G, Udawatta V. et al. Pre-Transplant Depression Is Associated with Length of Hospitalization, Discharge Disposition, and Survival after Liver Transplantation. PLoS One 2016; 11: e0165517
• 8 Sullivan LE, Fiellin DA, O’Connor PG. The prevalence and impact of alcohol problems in major depression: a systematic review. Am J Med 2005; 118: 330-341
• 9 Voican CS, Corruble E, Naveau S. et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014; 171: 404-415
• 10 Udina M, Castellvi P, Moreno-Espana J. et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry 2012; 73: 1128-1138
• 11 Wedemeyer H. [Treatment of hepatitis C: what is known?]. Internist (Berl) 2014; 55: 1419-1426
• 12 Wranke A, Wedemeyer H. Antiviral therapy of hepatitis delta virus infection – progress and challenges towards cure. Curr Opin Virol 2016; 20: 112-118
• 13 Blachier M, Leleu H, Peck-Radosavljevic M. et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013; 58: 593-608
• 14 Institut RK. Statistisches Jahrbuch In; 2015
• 15 Jablonka A, Solbach P, Wobse M. et al. Seroprevalence of antibodies and antigens against hepatitis A-E viruses in refugees and asylum seekers in Germany in 2015. Eur J Gastroenterol Hepatol 2017; 29: 939-945
• 16 Heidrich B, Wiegand SB, Buggisch P. et al. Treatment of naive patients with chronic hepatitis C genotypes 2 and 3 with pegylated interferon alpha and ribavirin in a real world setting: relevance for the new era of DAA. PloS one 2014; 9: e108751
• 17 Lonardo A, Ballestri S, Guaraldi G. et al. Fatty liver is associated with an increased risk of diabetes and cardiovascular disease – Evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol 2016; 22: 9674-9693
• 18 Younossi ZM, Stepanova M, Afendy M. et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011; 9: 524-530 e521.
• 19 Weiss J, Rau M, Geier A. Nichtalkoholische Fettlebererkrankung: Epidemiologie, Verlauf, Diagnostik und Therapie. Dtsch Arztebl Int 2014; 111: 447-452
• 20 Non-alcoholic Fatty Liver Disease Study Group. Lonardo A, Bellentani S. et al. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis 2015; 47: 997-1006
• 21 Cusi K, Sanyal AJ, Zhang S. et al. Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diabetes Obes Metab 2017 , DOI: 10.1111/dom.12973
• 22 Roeb E, Steffen HM, Bantel H. et al. [S2k Guideline non-alcoholic fatty liver disease]. Z Gastroenterol 2015; 53: 668-723
• 23 Grander C, Grabherr F, Moschen AR. et al. Non-Alcoholic Fatty Liver Disease: Cause or Effect of Metabolic Syndrome. Visc Med 2016; 32: 329-334
• 24 Ballestri S, Zona S, Targher G. et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 2016; 31: 936-944
• 25 Valbusa F, Bonapace S, Agnoletti D. et al. Nonalcoholic fatty liver disease and increased risk of 1-year all-cause and cardiac hospital readmissions in elderly patients admitted for acute heart failure. PLoS One 2017; 12: e0173398
• 26 WHO. Depression and Other Common Mental Disorders: Global Health Estimates. In. Genf: WHO; 2017
• 27 Charlson FJ, Moran AE, Freedman G. et al. The contribution of major depression to the global burden of ischemic heart disease: a comparative risk assessment. BMC Med 2013; 11: 250
• 28 Ferrari AJ, Somerville AJ, Baxter AJ. et al. Global variation in the prevalence and incidence of major depressive disorder: a systematic review of the epidemiological literature. Psychol Med 2013; 43: 471-481
• 29 Vancampfort D, Correll CU, Wampers M. et al. Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variables. Psychol Med 2014; 44: 2017-2028
• 30 Vancampfort D, Mitchell AJ, De Hert M. et al. Type 2 Diabetes in Patients with Major Depressive Disorder: A Meta-Analysis of Prevalence Estimates and Predictors. Depress Anxiety 2015; 32: 763-773
• 31 Cuijpers P, Vogelzangs N, Twisk J. et al. Differential mortality rates in major and subthreshold depression: meta-analysis of studies that measured both. Br J Psychiatry 2013; 202: 22-27
• 32 Mezuk B, Chen Y, Yu C. et al. Depression, anxiety, and prevalent diabetes in the Chinese population: findings from the China Kadoorie Biobank of 0.5 million people. J Psychosom Res 2013; 75: 511-517
• 33 Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J 2006; 27: 2763-2774
• 34 Pan A, Keum N, Okereke OI. et al. Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies. Diabetes Care 2012; 35: 1171-1180
• 35 Xu Q, Anderson D, Lurie-Beck J. The relationship between abdominal obesity and depression in the general population: A systematic review and meta-analysis. Obes Res Clin Pract 2011; 5: e267-360
• 36 Barboza KC, Salinas LM, Sahebjam F. et al. Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients. Metab Brain Dis 2016; 31: 869-880
• 37 Smith RS. The macrophage theory of depression. Med Hypotheses 1991; 35: 298-306
• 38 Dantzer R, O’Connor JC, Freund GG. et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56
• 39 Felger JC, Li Z, Haroon E. et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry 2016; 21: 1358-1365
• 40 Lamers F, Vogelzangs N, Merikangas KR. et al. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol psychiatry 2013; 18: 692-699
• 41 Leonard BE. Inflammation as the cause of the metabolic syndrome in depression. Mod Trends Pharmacopsychiatry 2013; 28: 117-126
• 42 Maes M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 664-675
• 43 Maes M, Berk M, Goehler L. et al. Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 2012; 10: 66
• 44 Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22-34
• 45 Penninx BW, Milaneschi Y, Lamers F. et al. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med 2013; 11: 129
• 46 Kappelmann N, Lewis G, Dantzer R. et al. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry 2016 , DOI: 10.1038/mp.2016.167
• 47 Cepeda MS, Stang P, Makadia R. Depression Is Associated With High Levels of C-Reactive Protein and Low Levels of Fractional Exhaled Nitric Oxide Results From the 2007–2012 National Health and Nutrition Examination Surveys. J Cin Psychiatry 2016; 77: 1666-1671
• 48 Hoyo-Becerra C, Huebener A, Trippler M. et al. Concomitant interferon alpha stimulation and TLR3 activation induces neuronal expression of depression-related genes that are elevated in the brain of suicidal persons. PLoS One 2013; 8: e83149
• 49 Raison CL, Rutherford RE, Woolwine BJ. et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013; 70: 31-41
• 50 Harrison NA, Brydon L, Walker C. et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009; 66: 407-414
• 51 Zheng P, Zeng B, Zhou C. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry 2016; 21: 786-796
• 52 Scalera A, Di Minno MN, Tarantino G. What does irritable bowel syndrome share with non-alcoholic fatty liver disease? World J Gastroenterol 2013; 19: 5402-5420 .
• 53 Macedo D, Filho AJ, Soares de Sousa CN. et al. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness. J Affect Disord 2017; 208: 22-32
• 54 Slyepchenko A, Maes M, Jacka FN. et al. Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities. Psychother Psychosom 2017; 86: 31-46
• 55 Slyepchenko A, Maes M, Machado-Vieira R. et al. Intestinal Dysbiosis, Gut Hyperpermeability and Bacterial Translocation: Missing Links Between Depression, Obesity and Type 2 Diabetes. Curr Pharm Des 2016; 22: 6087-6106
• 56 Jiang H, Ling Z, Zhang Y. et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 2015; 48: 186-194
• 57 Chen Y, Yang F, Lu H. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54: 562-572
• 58 Mutlu EA, Gillevet PM, Rangwala H. et al. Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver Physiol 2012; 302: G966-978
• 59 Tyakht AV, Dubinkina VB, Odintsova VY. et al. Data on gut metagenomes of the patients with alcoholic dependence syndrome and alcoholic liver cirrhosis. Data Brief 2017; 11: 98-102
• 60 Liu Y, Chen L, Zou Z. et al. Hepatitis C virus infection induces elevation of CXCL10 in human brain microvascular endothelial cells. J Med Virol 2016; 88: 1596-1603
• 61 de Wit NM, Vanmol J, Kamermans A. et al. Inflammation at the blood-brain barrier: The role of liver X receptors. Neurobiol Dis 2016 , DOI: 10.1016/j.nbd.2016.09.015
• 62 Jayakumar AR, Rama Rao KV, Norenberg MD. Neuroinflammation in hepatic encephalopathy: mechanistic aspects. J Clin Exp Hepatol 2015; 5: S21-28
• 63 Jayakumar AR, Tong XY, Curtis KM. et al. Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy. J Neurochem 2014; 128: 890-903
• 64 Zemtsova I, Gorg B, Keitel V. et al. Microglia activation in hepatic encephalopathy in rats and humans. Hepatology 2011; 54: 204-215
• 65 Garcia-Martinez R, Cordoba J. Acute-on-chronic liver failure: the brain. Curr Opin Crit Care 2011; 17: 177-183
• 66 Bokemeyer M, Ding XQ, Goldbecker A. et al. Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy. Gut 2011; 60: 370-377
• 67 Grover VP, Pavese N, Koh SB. et al. Cerebral microglial activation in patients with hepatitis C: in vivo evidence of neuroinflammation. J Viral Hepat 2012; 19: e89-96
• 68 Banerjee A, Abdelmegeed MA, Jang S. et al. Increased Sensitivity to Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats. PLoS One 2015; 10: e0140498
• 69 Bishehsari F, Saadalla A, Khazaie K. et al. Light/Dark Shifting Promotes Alcohol-Induced Colon Carcinogenesis: Possible Role of Intestinal Inflammatory Milieu and Microbiota. Int J Mol Sci 2016 17.
• 70 Chen P, Starkel P, Turner JR. et al. Dysbiosis-induced intestinal inflammation activates tumor necrosis factor receptor I and mediates alcoholic liver disease in mice. Hepatology 2015; 61: 883-894
• 71 Chiu WC, Huang YL, Chen YL. et al. Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats. Food Funct 2015; 6: 1692-1700
• 72 Gonzalez-Reimers E, Santolaria-Fernandez F, , Martin-Gonzalez MC. et al. Alcoholism: a systemic proinflammatory condition. World J Gastroenterol 2014; 20: 14660-14671
• 73 Kakiyama G, Hylemon PB, Zhou H. et al. Colonic inflammation and secondary bile acids in alcoholic cirrhosis. Am J Physiol Gastrointest Liver Physiol 2014; 306: G929-937
• 74 Leclercq S, Cani PD, Neyrinck AM. et al. Role of intestinal permeability and inflammation in the biological and behavioral control of alcohol-dependent subjects. Brain Behav Immun 2012; 26: 911-918
• 75 Neyrinck AM, Etxeberria U, Taminiau B. et al. Rhubarb extract prevents hepatic inflammation induced by acute alcohol intake, an effect related to the modulation of the gut microbiota. Mol Nutr Food Res 2017 61.
• 76 Leclercq S, De Saeger C, Delzenne N. et al. Role of inflammatory pathways, blood mononuclear cells, and gut-derived bacterial products in alcohol dependence. Biol Psychiatry 2014; 76: 725-733
• 77 Crews FT, Lawrimore CJ, Walter TJ. et al. The role of neuroimmune signaling in alcoholism. Neuropharmacology 2017 , DOI: DOI: 10.1016/j.neuropharm.2017.01.031
• 78 Crews FT, Vetreno RP. Neuroimmune basis of alcoholic brain damage. Int Rev Neurobiol 2014; 118: 315-357
• 79 Crews FT, Vetreno RP, Broadwater MA. et al. Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. Pharmacol Rev 2016; 68: 1074-1109
• 80 Crews FT, Walter TJ, Coleman Jr. LG. et al. Toll-like receptor signaling and stages of addiction. Psychopharmacology 2017 , DOI: DOI: 10.1007/s00213-017-4560-6
• 81 He J, Crews FT. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 2008; 210: 349-358
• 82 Bala S, Marcos M, Gattu A. et al. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLoS One 2014; 9: e96864
• 83 Damms-Machado A, Louis S, Schnitzer A. et al. Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction. Am J Clin Nutr 2017; 105: 127-135
• 84 Scarpellini E, Lupo M, Iegri C. et al. Intestinal permeability in non-alcoholic fatty liver disease: the gut-liver axis. Rev Recent Clin Trials 2014; 9: 141-147
• 85 Spengler E, Loomba R. The Gut Microbiota, Intestinal Permeability, Bacterial Translocation, and Nonalcoholic Fatty Liver Disease: What Comes First? Cell Mol Gastroenterol Hepatol 2015; 1: 129-130
• 86 Kirpich IA, Feng W, Wang Y. et al. The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res 2012; 36: 835-846
• 87 Kelly JR, Kennedy PJ, Cryan JF. et al. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci 2015; 9: 392
• 88 Moussaoui N, Jacobs JP, Larauche M. et al. Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex. J Neurogastroenterol Motil 2017; 23: 135-143
• 89 Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett 2008; 29: 117-124
• 90 Farhadi A, Banan A, Fields J. et al. Intestinal barrier: an interface between health and disease. J Gastroenterol Hepatol 2003; 18: 479-497
• 91 Bjarnason I, Peters TJ, Wise RJ. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet 1984; 1: 179-182
• 92 Leclercq S, de Timary P, Delzenne NM. et al. The link between inflammation, bugs, the intestine and the brain in alcohol dependence. Transl Psychiatry 2017; 7: e1048
• 93 Wiest R, Albillos A, Trauner M. et al. ‘Targeting the gut-liver axis in liver disease’. J Hepatol 2017 , DOI: 10.1016/j.jhep.2017.05.007
• 94 Zhu L, Baker RD, Baker SS. Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res 2015; 77: 245-251
• 95 Llopis M, Cassard AM, Wrzosek L. et al. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease. Gut 2016; 65: 830-839
• 96 Odena G, Chen J, Lozano JJ. et al. LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis. Sci Rep 2016; 6: 35610
• 97 Harte AL, da Silva NF, Creely SJ. et al. Elevated endotoxin levels in non-alcoholic fatty liver disease. J Inflamm (Lond) 2010; 07: 15
• 98 Kmiec Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol 2001; 161 Iii-xiii, 1-151
• 99 Patel S, Behara R, Swanson GR. et al. Alcohol and the Intestine. Biomolecules 2015; 5: 2573-2588
• 100 Trautwein C, Tacke F. SFB/TRR 57 Aachen/Bonn: Organfibrose – von den Mechanismen der Schädigung zur Beeinflussung der Krankheit. Z Gastroenterol 2017; 55: 310-312
• 101 Morton N, Seckl J. 11β-hydroxysteroid dehydrogenase type 1 and obesity. In Obesity and Metabolism: Karger Publishers; 2008: 146-164
• 102 Lyte M. The role of microbial endocrinology in infectious disease. J Endocrinol 1993; 137: 343-345
• 103 Gahr M, Zeiss R, Lang D. et al. Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms. J Clin Pharmacol 2016; 56: 769-778
• 104 Friedrich ME, Akimova E, Huf W. et al. Drug-Induced Liver Injury during Antidepressant Treatment: Results of AMSP, a Drug Surveillance Program. Int J Neuropsychopharmacol 2016: 19
• 105 Bunchorntavakul C, Reddy KR. Drug Hepatotoxicity: Newer Agents. Clin Liver Dis 2017; 21: 115-134
• 106 Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-223
• 107 Spina E, Trifiro G, Caraci F. Clinically significant drug interactions with newer antidepressants. CNS Drugs 2012; 26: 39-67
• 108 Li F, Chin C, Wangsa J. et al. Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride. Drug Metab Dispos 2012; 40: 1723-1735
• 109 Abou-Saleh MT, Muller-Oerlinghausen B, Coppen AJ. Lithium in the episode and suicide prophylaxis and in augmenting strategies in patients with unipolar depression. Int J Bipolar Disord 2017; 5: 11
• 110 Admon R, Kaiser RH, Dillon DG. et al. Dopaminergic Enhancement of Striatal Response to Reward in Major Depression. Am J Psychiatry 2017; 174: 378-386
• 111 Rosenzweig P, Canal M, Patat A. et al. A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol 2002; 17: 1-13
• 112 Karyotaki E, Riper H, Cuijpers P. Internet-Based Self-Help Interventions for Depression in Routine Care-Reply. JAMA Psychiatry 2017; 74: 853
• 113 Hengst J, Falk CS, Schlaphoff V. et al. Direct-Acting-Antiviral-Induced Hepatitis C Virus Clearance Does Not Completely Restore the Altered Cytokine and Chemokine Milieu in Patients With Chronic Hepatitis C. J Infect Dis. 2016; 214 (12) : 1965-1974
• 114 DGPPN, BÄK, KBV, AWMF (Hrsg.) für die Leitliniengruppe Unipolare Depression. S3-Leitlinie/Nationale VersorgungsLeitlinie Unipolare Depression – Langfassung, 2. Auflage. Version 5. 2015 [cited: 2017-08-10]. DOI: 10.6101/AZQ/000364. www.depression.versorgungsleitlinien.de ).