Clinical and Biochemical Manifestations of Depression (original) (raw)
Related papers
1988
Major depressive disorder (MDD) is a chronic, recurrent, and severe psychiatric disorder with high mortality and medical comorbidities. Stress-related pathways have been directly involved in the pathophysiology and treatment of MDD. The present paper provides an overview on the stress system as a model to understand key pathophysiological paradigms in MDD. These mechanisms involve behavioral, cognitive, and systemic manifestations and are also associated with the mechanisms of action of effective antidepressants. Aspects such as depression subtypes, inflammation, insulin resistance, oxidative stress, and prothrombotic states in critical brain circuits and periphery are critically appraised. Finally, new strategies for approaching treatment-resistant major depression and potential adverse effects associated with this complex and intricate network are highlighted. The authors used PubMed as the database for this review. Each author extracted relevant data and assessed the methodologic...
2015
Copyright © 2015 Phillip W. Gold et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Major depressive disorder (MDD) is a chronic, recurrent, and severe psychiatric disorder with high mortality and medical comorbidities. Stress-related pathways have been directly involved in the pathophysiology and treatment of MDD. The present paper provides an overview on the stress system as a model to understand key pathophysiological paradigms in MDD. These mechanisms involve behavioral, cognitive, and systemic manifestations and are also associated with the mechanisms of action of effective antidepressants. Aspects such as depression subtypes, inflammation, insulin resistance, oxidative stress, and prothrombotic states in critical brain circuits and periphery are critically appraised. Finally, new strategies for approaching tre...
Cellular consequences of stress and depression
Dialogues in clinical neuroscience, 2004
Stress is known to activate distinct neuronal circuits in the brain and induce multiple changes on the cellular level, including alterations in neuronal structures. On the basis of clinical observations that stress often precipitates a depressive disease, chronic psychosocial stress serves as an experimental model to evaluate the cellular and molecular alterations associated with the consequences of major depression. Antidepressants are presently believed to exert their primary biochemical effects by readjusting aberrant intrasynaptic concentrations of neurotransmitters, such as serotonin or noradrenaline, suggesting that imbalances viihin the monoaminergic systems contribute to the disorder (monoaminergic hypothesis of depression). Here, we reviev the results that comprise our understanding of stressful experience on cellular processes, with particular focus on the monoaminergic systems and structural changes within brain target areas of monoaminergic neurons.
Metabolic Brain Disease, 2009
Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may–at least partly–be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites–and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo–in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.
Editorial: (Neuro)inflammation and neuroprogression as new pathways and drug 3 targets in depression: From antioxidants to kinase inhibitors 4 5 20 2. Pro-inflammatory cytokines are able to cause depressive-like 21 behaviors (Smith, 1991); 22 3. Pro-inflammatory cytokines are able to explain the multicausal 23 etiology of depression whereby psychosocial stressors and internal 24 stressors (medical illnesses) may trigger depression ( Q2 Maes, 1997; 25 Yirmiya, 1997); 26 4. Pro-inflammatory cytokines are able to explain the serotonergic 27 disturbances in depression (Maes et al., 1993b, 1994); 28 5. Pro-inflammatory cytokines are able to explain disorders in the 29 hypothalamic-pituitary adrenal axis in depression (Maes et al., 1993a); 30 6. Pro-inflammatory cytokines are blocked by antidepressants (Xia 31 et al., 1996; Maes et al., 1999). 32 These statements were based on observations in depression made 33 between 1990 and 1995, e.g. statements 1, 4, and 5. Statements 2, 3 and 34 6 were theoretical deductions not yet proven by observations in 35 depression. For example, although the depressogenic effects of 36 cytokines were at that time not examined there was some evidence 37 that the somatic, and not the cognitive, symptoms of depression were 38 related to inflammatory markers indicating that depression may bear 39 some similarities with cytokine-induced illness-behavior (Maes, 40 1993). The effects of psychological stressors activating the cytokine 41 network were discovered in 1998-1999 (Maes et al., 1998) and 42 confirmed afterwards (Steptoe et al., 2001; Kiecolt-Glaser et al., 2003). 43 Many studies published over the last 15 years provided the 44 necessary evidence that the abovementioned 6 statements are indeed 45 correct and thus that the "monocyte-T lymphocyte" hypothesis of 46 depression should be accepted. This special issue offers state-of-the-47 0278-5846/$see front matter Neuronal cell death induced by antidepressants: lack of correlation with Egr-1, NF-369 kappa B and extracellular signal-regulated protein kinase activation. Biochem I, et al. N-acetyl cysteine for 372 depressive symptoms in bipolar disorder-a double-blind randomized placebo-373 controlled trial. Biol Psychiatry 2008;64(6):468-75. 374 Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways 375 underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative 376 stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35(3):804-17. 377 Bjarnason I, Takeuchi K. Intestinal permeability in the pathogenesis of NSAID-induced 378 enteropathy. J Gastroenterol 2009;44(Suppl 19):23-9. 379 Borders AS, de Almeida L, Van Eldik LJ, Watterson DM. The p38alpha mitogen-activated 380 protein kinase as a central nervous system drug discovery target. BMC Neurosci 381 2008;9(Suppl 2):S12. 382 Brasier AR. The NF-kappaB regulatory network. Cardiovasc Toxicol 2006;6(2):111-30. 383 Brunello N, Alboni S, Capone G, Benatti C, Blom JM, Tascedda F, et al. Acetylsalicylic acid 384 accelerates the antidepressant effect of fluoxetine in the chronic escape deficit 385 model of depression. Int Clin Psychopharmacol 2006;21(4):219-25. 386 Bumrungpert A, Kalpravidh RW, Chuang CC, Overman A, Martinez K, Kennedy A, et al. 387 Xanthones from mangosteen inhibit inflammation in human macrophages and in 388 human adipocytes exposed to macrophage-conditioned media. J Nutr 2010;140 389 (4):842-7. 390 Chung YC, Kim SR, Jin BK. Paroxetine prevents loss of nigrostriatal dopaminergic 391 neurons by inhibiting brain inflammation and oxidative stress in an experimental 392 model of Parkinson's disease. J Immunol 2010;185(2):1230-7. 393 Connor TJ, Kelliher P, Shen Y, Harkin A, Kelly JP, Leonard BE. Effect of subchronic 394 antidepressant treatments on behavioral, neurochemical, and endocrine changes in 395 the forced-swim test. Pharmacol Biochem Behav 2000;65(4):591-7. 396 Diamond M, Kelly JP, Connor TJ. Antidepressants suppress production of the Th1 397 cytokine interferon-gamma, independent of monoamine transporter blockade. Eur 398 Neuropsychopharmacol 2006;16(7):481-90. 399 Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN. Reduced 400 activation and expression of ERK1/2 MAP kinase in the post-mortem brain of 401 depressed suicide subjects. J Neurochem 2001;77(3):916-28. 402 Feng P, Guan Z, Yang X, Fang J. Impairments of ERK signal transduction in the brain in a 403 rat model of depression induced by neonatal exposure of clomipramine. Brain Res 404 2003;991(1-2):195-205. 405 Geffard M, de Bisschop L, Duleu S, Hassaine N, Mangas A, Coveñas R. Endotherapia: a 406 new frontier in the treatment of multiple sclerosis and other chronic diseases. 407 Discov Med 2010;10(54):443-51. 408 Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW. Depression is 409 associated with decreased 25-hydroxy vitamin D and increased parathyroid 410 hormone levels in older adults. Arch Gen Psychiatry 2008;65(5):508-12. 411 Igaz P, Tóth S, Falus A. Biological and clinical significance of the JAK-STAT pathway; 412 lessons from knockout mice. Inflamm Res 2001;50(9):435-41. 413 Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory 414 therapy-from molecular mechanisms to therapeutic benefits. Biochim Biophys 415 Acta 2005;1754(1-2):253-62. 416 Kennedy SH, Segal ZV, Cohen NL, Levitan RD, Gemar M, Bagby RM. Lithium carbonate versus 417 cognitive therapy as sequential combination treatment strategies in partial responders 418 to antidepressant medication: an exploratory trial. J Clin Psychiatry 2003;64(4):439-44.
Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychopharmacology, 2016
The neuroinflammation perspective of depression: reuniting the outstanding mechanisms of the pathophysiology Major Depressive Disorder (MDD) is a serious mental health problem that leads to patients' disability and has huge impact on social and economic burden to society. The current available medications for the treatment of depression are mainly targeted on enhancing monoamine neurotransmission. However, antidepressant treatments are still lacking high efficacy in many cases which is associated with low treatment response and remission rates. However, the latest knowledge regarding the pathophysiology of depression indicates that depression is developed by highly complex and integrated mechanisms in which monoaminergic deficiency could only be part of. The paradigm is now shifting from monoaminergic hypothesis to significance of other novel mechanisms that could possibly play substantial role for the development of depression in a highly interrelated manner. In fact, neuroinflammation, amongst other mechanisms does seem to be a key pathological component by having impact on certain pathway pathologies including glutamatergic neurotransmission, oxidative processes, neurotropic factors, neurotransmitter metabolism, and glucocorticoid functions in the central nervous system (CNS) and in the periphery, thereby triggers the pathological alterations that is thought to contribute to the development of depression. The neuroinflammation comprehends the processes exampled from excessive pro-inflammatory cytokine release to activation of microglia and indolamine 2,3-dioxygenase (IDO) pathway, excessive glutamatergic neurotransmission, hyperactive hypothalamus-pituitary-adrenal (HPA) axis, decreased neurogenesis and synaptic plasticity. In fact, the antidepressant effect of ketamine as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist might be at least partially linked to inflammatory modulations. The significance of inflammation in depression is not only mentioned by the literature of basic researches from a mechanistic aspect but also by the possible clinical implications suggested by the clinical reports. Although the exact role of inflammation in depression and its clinical translation have not been determined yet, the inflammationmediated point of view might provide novel insights for improving the diagnosis at clinic (e.g., inflammatory biomarkers), predicting antidepressant treatment response and thereby re-evaluating the treatment strategy. Moreover, with all that, the inflammation aspect raises the question for the possible significance of utilizing anti-inflammatory approaches in the treatment of depression.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2011
Editorial: (Neuro)inflammation and neuroprogression as new pathways and drug 3 targets in depression: From antioxidants to kinase inhibitors 4 5 20 2. Pro-inflammatory cytokines are able to cause depressive-like 21 behaviors (Smith, 1991); 22 3. Pro-inflammatory cytokines are able to explain the multicausal 23 etiology of depression whereby psychosocial stressors and internal 24 stressors (medical illnesses) may trigger depression ( Q2 Maes, 1997; 25 Yirmiya, 1997); 26 4. Pro-inflammatory cytokines are able to explain the serotonergic 27 disturbances in depression (Maes et al., 1993b, 1994); 28 5. Pro-inflammatory cytokines are able to explain disorders in the 29 hypothalamic-pituitary adrenal axis in depression (Maes et al., 1993a); 30 6. Pro-inflammatory cytokines are blocked by antidepressants (Xia 31 et al., 1996; Maes et al., 1999). 32 These statements were based on observations in depression made 33 between 1990 and 1995, e.g. statements 1, 4, and 5. Statements 2, 3 and 34 6 were theoretical deductions not yet proven by observations in 35 depression. For example, although the depressogenic effects of 36 cytokines were at that time not examined there was some evidence 37 that the somatic, and not the cognitive, symptoms of depression were 38 related to inflammatory markers indicating that depression may bear 39 some similarities with cytokine-induced illness-behavior (Maes, 40 1993). The effects of psychological stressors activating the cytokine 41 network were discovered in 1998-1999 (Maes et al., 1998) and 42 confirmed afterwards (Steptoe et al., 2001; Kiecolt-Glaser et al., 2003). 43 Many studies published over the last 15 years provided the 44 necessary evidence that the abovementioned 6 statements are indeed 45 correct and thus that the "monocyte-T lymphocyte" hypothesis of 46 depression should be accepted. This special issue offers state-of-the-47 0278-5846/$see front matter Neuronal cell death induced by antidepressants: lack of correlation with Egr-1, NF-369 kappa B and extracellular signal-regulated protein kinase activation. Biochem I, et al. N-acetyl cysteine for 372 depressive symptoms in bipolar disorder-a double-blind randomized placebo-373 controlled trial. Biol Psychiatry 2008;64(6):468-75. 374 Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, et al. Pathways 375 underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative 376 stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35(3):804-17. 377 Bjarnason I, Takeuchi K. Intestinal permeability in the pathogenesis of NSAID-induced 378 enteropathy. J Gastroenterol 2009;44(Suppl 19):23-9. 379 Borders AS, de Almeida L, Van Eldik LJ, Watterson DM. The p38alpha mitogen-activated 380 protein kinase as a central nervous system drug discovery target. BMC Neurosci 381 2008;9(Suppl 2):S12. 382 Brasier AR. The NF-kappaB regulatory network. Cardiovasc Toxicol 2006;6(2):111-30. 383 Brunello N, Alboni S, Capone G, Benatti C, Blom JM, Tascedda F, et al. Acetylsalicylic acid 384 accelerates the antidepressant effect of fluoxetine in the chronic escape deficit 385 model of depression. Int Clin Psychopharmacol 2006;21(4):219-25. 386 Bumrungpert A, Kalpravidh RW, Chuang CC, Overman A, Martinez K, Kennedy A, et al. 387 Xanthones from mangosteen inhibit inflammation in human macrophages and in 388 human adipocytes exposed to macrophage-conditioned media. J Nutr 2010;140 389 (4):842-7. 390 Chung YC, Kim SR, Jin BK. Paroxetine prevents loss of nigrostriatal dopaminergic 391 neurons by inhibiting brain inflammation and oxidative stress in an experimental 392 model of Parkinson's disease. J Immunol 2010;185(2):1230-7. 393 Connor TJ, Kelliher P, Shen Y, Harkin A, Kelly JP, Leonard BE. Effect of subchronic 394 antidepressant treatments on behavioral, neurochemical, and endocrine changes in 395 the forced-swim test. Pharmacol Biochem Behav 2000;65(4):591-7. 396 Diamond M, Kelly JP, Connor TJ. Antidepressants suppress production of the Th1 397 cytokine interferon-gamma, independent of monoamine transporter blockade. Eur 398 Neuropsychopharmacol 2006;16(7):481-90. 399 Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN. Reduced 400 activation and expression of ERK1/2 MAP kinase in the post-mortem brain of 401 depressed suicide subjects. J Neurochem 2001;77(3):916-28. 402 Feng P, Guan Z, Yang X, Fang J. Impairments of ERK signal transduction in the brain in a 403 rat model of depression induced by neonatal exposure of clomipramine. Brain Res 404 2003;991(1-2):195-205. 405 Geffard M, de Bisschop L, Duleu S, Hassaine N, Mangas A, Coveñas R. Endotherapia: a 406 new frontier in the treatment of multiple sclerosis and other chronic diseases. 407 Discov Med 2010;10(54):443-51. 408 Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW. Depression is 409 associated with decreased 25-hydroxy vitamin D and increased parathyroid 410 hormone levels in older adults. Arch Gen Psychiatry 2008;65(5):508-12. 411 Igaz P, Tóth S, Falus A. Biological and clinical significance of the JAK-STAT pathway; 412 lessons from knockout mice. Inflamm Res 2001;50(9):435-41. 413 Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory 414 therapy-from molecular mechanisms to therapeutic benefits. Biochim Biophys 415 Acta 2005;1754(1-2):253-62. 416 Kennedy SH, Segal ZV, Cohen NL, Levitan RD, Gemar M, Bagby RM. Lithium carbonate versus 417 cognitive therapy as sequential combination treatment strategies in partial responders 418 to antidepressant medication: an exploratory trial. J Clin Psychiatry 2003;64(4):439-44.
Oxidative stress, inflammation and treatment response in major depression
Psychoneuroendocrinology, 2016
Increased inflammation and oxidative stress have been shown in Major Depressive Disorder (MDD), although there is significant heterogeneity across studies. Whether markers of inflammation and oxidative stress are associated with antidepressant treatment response in MDD is currently unclear. The goals of the present study are to investigate markers of inflammation and oxidative stress in unmedicated MDD subjects and controls and test the relationship between these markers and antidepressant response in MDD subjects. Interleukin (IL)-6, tumor necrosis factor (TNF)-α, C-reactive protein, F2-isoprostanes, 8-OH 2-deoxyguanosine (8-OHdG), glutathione peroxidase, glutathione, and vitamin C were quantified in blood samples from 50 unmedicated MDD subjects and 55 healthy controls. Depression symptom severity was rated with the 17-item Hamilton Depression Rating Scale (HDRS). All subjects were somatically healthy and free from medications that could interfere with inflammation and oxidative s...