Article

Different immune patterns in melancholic and non-melancholic major depression

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

The search for immune patterns in major depression has thus far resulted in ambiguous findings, probably because patient samples are psychiatrically heterogeneous. We therefore focused on a detailed classification of subtypes of major depression, comparing patients with melancholic and non-melancholic major depression. Inpatients suffering from acute major depression were diagnosed and subclassified according to DSM IV criteria. Cell counts were determined by FACS analysis and morphology. Cytokine production (IL-2, IFN-γ, IL-10) upon mitogen stimulation was measured by ELISA in a whole blood assay. Non-melancholic patients showed increased counts of leukocytes, lymphocytes and NK-cells in the acute stage of disease and after two and four weeks of treatment. Their lymphokine production was unchanged compared to that of healthy controls. Melancholic patients on the other hand demonstrated normal cell counts but a decreased production of IL-2, IFN-γ and IL-10 during the acute stage of disease followed by a normalization with clinical improvement. Melancholic and non-melancholic patients showed different immune patterns. Classifying melancholic and non-melancholic patients is helpful towards the identification of immune characteristics typical for these diseases.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Thus, though the pathophysiology of MDD involving neuropeptides is mainly manifested in the CNS, changes of stress-related neuropeptides and inflammatory cytokines in the periphery may be exploited for diagnostic purposes in blood samples Holzer et al., 2012;Kormos and Gaszner, 2013;Wu et al., 2011;Werner and Covenas, 2010;Madaan and Wilson, 2009;Eaton et al., 2007;Aan Het et al., 2009). Therefore, it may be possible to differentiate between melancholic and nonmelancholic depressed patients by analyzing DPP4 activity, and a combination of cytokines and stress hormones/neuropeptides that are specific for each subgroup (Kaestner et al., 2005;Rothermundt et al., 2001;Westrin et al., 1998Westrin et al., , 1999. Analysis of blood cells appears to be less appropriate as controversial data was obtained in literature as outlined in Table 4 (Rothermundt et al., 2001). ...
... Therefore, it may be possible to differentiate between melancholic and nonmelancholic depressed patients by analyzing DPP4 activity, and a combination of cytokines and stress hormones/neuropeptides that are specific for each subgroup (Kaestner et al., 2005;Rothermundt et al., 2001;Westrin et al., 1998Westrin et al., , 1999. Analysis of blood cells appears to be less appropriate as controversial data was obtained in literature as outlined in Table 4 (Rothermundt et al., 2001). The link between neuropeptides and immunology with respect to depression has been described elsewhere and the importance of DPP4 in the immune response has been recently reviewed Farzi et al., 2015;Maes et al., 2009;Wagner et al., 2015a;Klemann et al., 2016;Waumans et al., 2015). ...
... Maes et al. (1996),Elgun et al. (1999aElgun et al. ( , 1999b present study a ambiguous results based on 39 articles as summarized byRothermundt et al. (2001), LI-NPY, immunolinked NPY. ...
... Zytokinsekretion und vermehrter Tagesmüdigkeit (Vgontzas et al. 1999 Mit diesen präklinischen Befunden in Einklang stehen klinischen Untersuchungen, die immunologische Unterschiede beschrieben haben zwischen melancholischen und nicht melancholischen Patienten (Rothermundt et al. 2001a;Rothermundt et al. 2001b), und zwischen depressiven Patienten mit atypischen und nicht atypischen Merkmalen (Anisman et al. 1999a;Anisman and Merali 2002). Dabei wurde insbesondere für IL-1β eine positive Assoziation beschrieben mit der Chronizität depressiver Symptome und einem frühen Krankheitsbeginn (Anisman et al. 1999b). ...
... ). Obwohl verschiedene Studien auch die Zytokinsekretion in Abhängigkeit von den klinischen Merkmalen (atypische vs nicht atypische und melancholische Depression und Dysthymie) untersucht haben(Anisman et al. 1999a;Rothermundt et al. 2001a;Rothermundt et al. 2001b;Zaharia et al. 2000), scheint bisher eine sichere Abgrenzung dieser Unterformen der Depression anhand des Zytokinprofils nicht möglich. Basierend auf den vorliegenden Befunden erscheint jedoch die Vermutung berechtigt, dass eine mässige aber chronische pro-inflammatorische Zytokinsekretion im Sinne einer Th1 Immunreaktion, die durch eine verminderte HPA Aktivität begünstigt wird(Elenkov and Chrousos 2002), zu der Entwicklung einer atypischer Depression beitragen kann (siehe Abbildung 30).Andererseits können pro-inflammatorische, aber auch anti-inflammatorische Zytokine die CRH Sekretion stimulieren(Barkhudaryan and Dunn 1999;Huitinga et al. 2000;Leonard 2001;Opp and Imeri 2001;Smith et al. 1999). ...
Thesis
Die schlafendokrine Regulation wird massgeblich beeinflusst durch Hirnareale, die auch für die Pathophysiologie psychiatrischer, und insbesondere affektiver Störungen, eine wichtige Rolle spielen. Dazu zählen neben dem Hypothalamus, und insbesondere dem paraventrikulären Kerngebiet (PVN), auch limbische Areale wie der Hippokampus und die Amygdala, der präfrontale Kortex sowie die afferenten Kerngebiete im Hirnstamm, insbesondere der Locus coeruleus (LC) und die Raphe Kerne. Der Schlaf und die nächtliche Hormonsekretion können als dynamische Prozesse begriffen werden, die gekennzeichnet sind durch eine fein abgestimmte Abfolge neuronaler Aktivitäten in bestimmten Kerngebieten im Verlauf einer Nacht. Somit ermöglichen polysomnographische und endokrine Untersuchungen Aussagen über mögliche Funktionsänderungen im Zusammenspiel dieser verschiedenen Kerngebiete und leisten daher einen wichtigen Beitrag für die (neuro-) psychiatrische Forschung. In der folgenden Arbeit haben wir insbesondere die dynamischen Aspekte der Schlafarchitektur und die nächtliche Hormonsekretion als Parameter verwendet, um verschiedene Einflussfaktoren auf die schlafendokrine Regulation zu untersuchen. Dabei war es mein Ziel, neben der Diagnose Major Depression auch eine Interaktion zwischen Geschlecht, Alter und Symptomatologie der Depression zu untersuchen. Wir haben dargestellt, dass das Geschlecht einen massgeblichen Einfluss auf diejenigen Schlafparameter ausübt, die bisher als charakteristische Merkmale einer Major Depression angesehen wurden. Weiterhin konnten wir zeigen, dass das Alter (bzw. die Menopause bei Frauen) die schlafendokrinen Veränderungen im Rahmen einer Major Depression geschlechtsspezifisch moduliert. Auch beobachteten wir, dass die klinischen Merkmale einer Major Depression durch geschlechtsspezifische Faktoren beeinflusst werden, wie auch neuere Studien nahelegen. Insbesondere stellen wir die Hypothese auf, dass sogenannte atypische Symptome der Depression bei jüngeren Frauen gehäuft vorkommen und in einer Unteraktivität der HPA Achse (vielleicht als Ausdruck einer genetischen Untererregbarkeit), der afferenten, aktivierenden Serotoninneurone und der Amygdala Kerne begründet liegen. An dieser Konstellation könnte auch eine chronische, aber moderate inflammatorische Immunreaktion beteiligt sein. Im Gegensatz dazu weisen Patienten mit nicht atypischer Depression Zeichen einer Überaktivität der HPA Achse und der Amygdala Kerne auf, die sich im Sinne eines Teufelskreises gegenseitig verstärken und afferente katecholaminerge Neurone einbeziehen können. Die Möglichkeit, dass eine durch inflammatorische Zytokine hervorgerufene Sensibilisierung der HPA Aktivität zu dieser Entwicklung beiträgt scheint plausibel und sollte in zukünftigen Studien überprüft werden. Die unmittelbare Relevanz dieser Überlegungen und Befunde wird unterstrichen durch geschlechtsspezifische Behandlungserfolge bei Patienten mit Major Depression und durch unsere Befunde einer geschlechtsspezifischen Beeinflussung der schlafendokrinen Regulation durch Peptidhormone. Schliesslich haben wir in einer Gruppe von Patientinnen mit Multipler Sklerose (MS) gezeigt, dass unabhängig von den Symptomen einer Major Depression, die hochdosierte Gabe von Glukokortikoiden depressions-typische Veränderungen der schlafendokrinen Regulation induzieren kann. Da diese Patientinnen neben der akuten Glukokortikoidgabe auch eine akute inflammatorische Reaktion (akuter MS Schub) aufwiesen, stellt sich die Frage nach einer Interaktion zwischen der inflammatorischen Reaktion und der Hypothalamus-Hypophysen-Nebennierenrinden (HPA) Achse. Einerseits können immunologische Prozesse den Schlaf beeinflussen, und andererseits gibt es zunehmend Hinweise für einen Zusammenhang zwischen affektiven Symptomen und Immunreaktionen. Da das Geschlecht Immunreaktionen wesentlich beeinflusst, könnten die geschlechtsspezifischen Unterschiede hinsichtlich der klinischen Symptome und der schlafendokrinen Veränderungen im Rahmen einer Major Depression Ausdruck unterschiedlicher zugrundeliegender immunologischer Mechanismen sein. Unterschiede in der Pathophysiologie depressiver Störungen eröffnen die Möglichkeit, die Therapie depressiver Patienten spezifischer auf die zugrundeliegenden Pathomechanismen auszurichten. Dadurch könnten erstens die Behandlung optimiert und zweitens neue spezifischere Behandlungsstrategien für Patienten mit affektiven Störungen entwickelt werden.
... Chronic stress can also result in dysregulation with activation or suppression of the immune system; clinical and pre-clinical research support a role of immune system dysregulation in MDD with activation of the cellular and humoral immune responses (Kronfol & Remick, 2000;Licinio & Wong, 1999). Increased circulating lymphocytes and monocytes have been described (Herbert & Cohen, 1993;Rothermundt, 2001;Seidel, 1996). Increased circulating IL-6 levels have been described in MDD and these levels were significantly correlated with self-reported mood ratings (Alesci, 2005). ...
... Nevertheless, different types of MDD may exhibit divergent immune profiles, and decreased Th1 activation has been described in melancholic depressed patients, which is accompanied by a marked HPA axis activation. Non-melancholic MDD patients show increased inflammation features with elevated monocyte count and levels of IL-1ß and α2-macroglobulin (Kaestner, 2005;Rothermundt, 2001). Post-partum depression also shows a predominance of Th1 activation (Maes, 2002;Ostensen, 2005), and symptoms of anxiety and depression in the early post-partum period are related to increased levels of pro-inflammatory cytokine IL-8 (Maes, 2002). ...
... Moreover, few longitudinal studies have examined depressive subtypes (Rothermundt et al. 2001;Kaestner et al. 2005;Yoon et al. 2012;Lamers et al. 2013;Glaus et al. 2014;Rudolf et al. 2014) that have been shown to be highly heterogeneous (Schmidt et al. 2011;Lopresti et al. 2014) and even fewer studies have considered the well-established comorbidity among mental disorders (Stewart et al. 2009;Kivimaki et al. 2014) or current v. past disorders (Whooley et al. 2008). ...
... Future studies with more closely timed follow-up assessments may inform potential mechanisms for elevation of hsCRP among those with this condition. Our finding of unidirectional associations between MDD and elevated hsCRP levels appear to be specific to the atypical subtype of MDD, which is characterized by somatic symptoms including sleep, energy and eating behavior (Rothermundt et al. 2001;Kaestner et al. 2005;Stewart et al. 2009;Duivis et al. 2011;Copeland et al. 2012;Lamers et al. 2013;Glaus et al. 2014;Hickman et al. 2014;Rudolf et al. 2014;Schmidt et al. 2014). This finding suggests that the atypical MDD is associated with more detectable immune dysfunction. ...
Article
Background There has been increasing evidence that chronic low-grade inflammation is associated with mood disorders. However, the findings have been inconsistent because of heterogeneity across studies and methodological limitations. Our aim is to prospectively evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)- α and high sensitivity C-reactive protein (hsCRP) with mood disorders. Methods The sample consisted of 3118 participants (53.7% women; mean age: 51.0, s.d. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, s.d. 0.6). Current and remitted mood disorders including bipolar and major depressive disorders (MDD) and its subtypes (atypical, melancholic, combined atypical and melancholic, and unspecified) were based on semi-structured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. Associations were tested by multiple linear and logistic regression models. Results Current combined MDD [ β = 0.29, 95% confidence interval (CI) 0.03–0.55] and current atypical MDD ( β = 0.32, 95% CI 0.10–0.55) at baseline were associated with increased levels of hsCRP at follow-up. There was little evidence for inflammation markers at baseline predicting mood disorders at follow-up. Conclusions The prospective unidirectional association between current MDD subtype with atypical features and hsCRP levels at follow-up suggests that inflammation may be a consequence of this condition. The role of inflammation, particularly hsCRP that is critically involved in cardiovascular diseases, warrants further study. Future research that examines potential influences of medications on inflammatory processes is indicated.
... The control groups consist of healthy subjects (Grosse et al., 2016;Rush et al., 2016) or patients suffering from NMD (Rothermundt et al., 2001). ...
... With regard to immunological abnormalities, a first study by Rothermundt and colleagues (Rothermundt et al., 2001) showed that patients with MD presented lower absolute monocyte in MD compared to HC; in the same manuscript the authors reported also a prominent rise up of Treg cells in patients after 7 weeks of antidepressant treatment (p <0.001). A further study (Rush et al., 2016) found the presence of higher levels of the pro-inflammatory cytokine IL-6 (p = 0.008) and lower levels of the regulatory cytokine TGF-β (p = 0.039) in patients with MD than HC; these 6 6 abnormalities did not achieve normalization after ECT. ...
Article
Background Melancholic depression (MD) is a subtype of Major Depression associated with more clinical severity and poorer prognosis that non-melancholic depression (NMD). The differentiation between depression subtypes is still clinical, although the identification of specific biomarkers could be useful for diagnosis and the development of new treatments. Purpose of the present manuscript is to review the biomarkers that have been associated with MD. Methods We performed a bibliographic research on the main databases (PubMed, Embase, PsycInfo, Isi Web of Knowledge, Medscape, The Cochrane Library), in order to find studies that proposed biological markers for melancholic depression. A total of 14 studies met our inclusion criteria. Results Most of studies focused on immune dysregulation. Subjects with MD show biological abnormalities than healthy controls (HC). MD might be characterized by specific biological changes and it could be associated to more severe abnormalities with respect to NMD; however especially about this latter point the available data are preliminary. Limitations Most available data have not been replicated; the studies focused on different biomarkers. In addition, many articles report results on a limited sample size. Conclusions Melancholic depression is a subtype of major depression that seems to be associated with specific alterations of different biological systems. Future studies with larger sample can confirm the results and hypothesis presented in this review.
... Only 5 out of a total of 23 studies were found to have carried out T cell subtyping. While three studies showed an increase in the % of CD4+ T cells, only two studies reported an increased CD4/CD8 ratio (Maes et al. 1992a), (Muller et al. 1993) (Darko et al. 1989;Seidel et al. 1996;Rothermundt et al. 2001). Interestingly only one study simultaneously measured in vitro T cell proliferation, which remained unchanged between MDD patients and controls (Darko et al. 1989). ...
... Other limiting factors include methodological limitations coupled with limited sample number as well as including diversity on self-report and clinician rated measures of depression severity. Sub-classifications of MDD into distinct clinical subtypes including minor, simple major and melancholic (Rothermundt et al. 2001) may be useful as different subgroups of MDD may be characterised by different T cell responses. Furthermore, the majority of studies retrieved were cross-sectional, which would exclude measurements of T cell changes at different stages of MDD or only be representative of the T cell response at one particular stage. ...
Article
Full-text available
Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the well-characterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better understanding of both the neuro- degenerative and -regenerative repair functions as present within the neuroimmune network during depression. Furthermore T cells may be important players in restoration of normal behaviour and immune cell homeostasis in depression.
... Accumulating evidence supports the idea that increased inflammatory markers are only present in a subgroup of depressed individuals in which immune processes are especially relevant to MDD development (Raison and Miller, 2011;Rothermundt et al., 2001) and presumably even treatment (Raison et al., 2013;Carvalho et al., 2013). Still, a valid clinical definition of this subgroup is pending. ...
Article
Increased inflammatory activation might only be present in a subgroup of depressed individuals in which immune processes are especially relevant to disease development. We aimed to analyze demographic, depression, and trauma characteristics of major depressive disorder (MDD) patients with regard to inflammatory monocyte gene expression. Fifty-six naturalistically treated MDD patients (32 ±12 years) and 57 healthy controls (HC; 31 ±11 years) were analyzed by the Inventory of Depressive Symptomatology (IDS) and by the Childhood Trauma Questionnaire (CTQ). We determined the expression of 38 inflammatory and immune activation genes including the glucocorticoid receptor (GR)α and GRβ genes in purified CD14(+) monocytes using quantitative-polymerase chain reaction (RT-qPCR). Monocyte gene expression was age-dependent, particularly in MDD patients. Increased monocyte gene expression and decreased GRα/β ratio were only present in MDD patients aged ⩾28 years. Post hoc analyses of monocyte immune activation in patients <28 years showed two subgroups: a subgroup with a severe course of depression (recurrent type, onset <15 years) - additionally characterized by panic/arousal symptoms and childhood trauma - that had a monocyte gene expression similar to HC, and a second subgroup with a milder course of the disorder (73% first episode depression, onset ⩾15 years) - additionally characterized by the absence of panic symptoms - that exhibited a strongly reduced inflammatory monocyte activation compared to HC. In conclusion, monocyte immune activation was not uniformly raised in MDD patients but was increased only in patients of 28 years and older.
... 4 A decreased lymphocyte response to mitogen stimulation and disorders in neutrophil activity has been observed in depression. [29][30][31] In mice having undergone an olfactory bulbectomy and in various models of learned helplessness, neutrophil phagocytosis was indicated to be a sensory determinant of stress response. 32 The number, serum concentration and proliferation of lymphocytes, B-cells and T-cells decrease in MDD. ...
... With regard to the here found decreased percentages of NK cells in MDD patients, there are early meta-analyses showing a lower activity and quantity of NK cells in MDD (Zorrilla et al., 2001). Yet, normal and higher activities of the NK cell system have also been found, as reviewed by Blume et al. (2011) and there are data indicating that the NK cell system and T cell system might be differentially affected in melancholic and non-melancholic subtypes of MDD (Rothermundt et al., 2001). ...
Article
Background: In a previous study, we found an up-regulated inflammatory monocyte gene expression profile in major depressive disorder (MDD) patients aged ⩾ 28 years and a down-regulated inflammatory gene expression profile in MDD patients aged < 28 years. In the same sample of patients, we aimed to investigate immune dysregulation in the lymphocyte arm of the immune system, particularly in the context of the described monocyte (de-)activation states. Methods: From deep frozen leukocytes, circulating percentages of monocytes, lymphocytes, B, T, and natural killer (NK) cells, and various functional subsets of T and T helper (Th) cells (Th1, Th2, Th17, and natural T regulatory cells) were measured in N = 50 MDD patients and N = 58 age- and gender-matched healthy controls (HC). In addition, serum levels of interleukin (IL)-6, sCD25, IL-7, IL-3, SCF, IGF-BP2, and EGF were evaluated. Results: MDD patients were in general characterized by an impaired maturation of Th2 cells, Th17 cells, and NK cells and by decreased serum levels of IL-7 and sCD25. MDD patients aged ⩾ 28 years additionally exhibited decreased percentages of CD4(+)CD25(high)FoxP3(+) T regulatory cells, next to signs of the above described partial T cell defects. Natural T regulatory cells were inversely associated with the pro-inflammatory state of the monocytes (r = -.311; p = .034) that characterized this patient subgroup. Conclusions: Deficiencies of the NK and T (regulatory) cell system and inflammatory monocyte immune activation co-occur as partly interrelated phenomena within the same MDD patients.
... In principal, it is likely that specific types of depression may be more frequently associated with higher or lower microglial activation status. For example, patients with depression due to a general medical condition were found to have high levels of inflammatory markers and microglial status, whereas patients with melancholic depression exhibited lower levels of inflammatory cells and markers than patients with non-melancholic depression [170,171]. Figure 3. Deviations From Microglial Homeostasis Induce Depression: Therapeutic Implications. Normal physiological functioning of microglia is essential for normal mood levels. ...
Article
Despite decades of intensive research, the biological mechanisms that causally underlie depression are still unclear, and therefore the development of novel effective antidepressant treatments is hindered. Recent studies indicate that impairment of the normal structure and function of microglia, caused by either intense inflammatory activation (e.g., following infections, trauma, stroke, short-term stress, autoimmune or neurodegenerative diseases) or by decline and senescence of these cells (e.g., during aging, Alzheimer's disease, or chronic unpredictable stress exposure), can lead to depression and associated impairments in neuroplasticity and neurogenesis. Accordingly, some forms of depression can be considered as a microglial disease (microgliopathy), which should be treated by a personalized medical approach using microglial inhibitors or stimulators depending on the microglial status of the depressed patient. Microglia are best known as the immune cells of the brain, but emerging data indicate that they also influence brain development, synaptic plasticity, neurogenesis, memory, and mood under quiescent physiological conditions.Deviation from microglial homeostasis, caused either by microglial activation during inflammatory conditions (e.g., infections, stress, stroke, or neurodegenerative diseases) or by microglial decline and senescence (e.g., during aging or chronic unpredictable stress), can lead to depression.Conventional antidepressant drugs and electroconvulsive therapy modulate microglial structure and function, suggesting a novel mechanism of action for these treatments.Microglia represent a promising therapeutic target for the treatment of depression; either microglia-suppressing or -stimulating drugs can serve as antidepressants, depending on the microglial status of the patient.
... According to (40), some individuals with depression may be more likely to exhibit an inflammatory biotype. For instance, it has been reported that individuals with depression who have melancholic traits have a distinct inflammatory profile compared to individuals without melancholic features (41). Moreover, distinct inflammatory profiles may also be linked to different depression subtypes (42)(43)(44). ...
Article
Full-text available
There is interest in the role of peripheral interleukin-6 (IL-6) in depression and the effect of treatment (e. g., pharmacologic, psychosocial, neurostimulation). However, the relationship between cognitive behavioral therapy (CBT), IL-6 and depression has not yet been established. We conducted a meta-analysis to explore the association between CBT and change of peripheral IL-6 levels in depressive symptoms or major depressive disorder (MDD). A systematic search of online databases (i.e., PubMed, Web of Science, Google Scholar, PsycINFO, and Cochrane Library) was completed from inception to May 2021. In total, 10 eligible papers with 940 participants reporting peripheral IL-6 levels before and after CBT were included in the analysis. The main result indicates that peripheral levels of IL-6 were significantly lower after CBT intervention in individuals with depression, with a small effect (SMD = 0.38, 95% CI: 0.07, 0.69, p = 0.02). The results of subgroup analyses demonstrate that (1) there was a significant decrease in IL-6 for studies that were equal to or <8 weeks in duration vs. more than 8 weeks in duration, and (2) IL-6 was significantly reduced in the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis (i.e., DSM-IV, DSM-IV-TR, or DSM-V) of MDD, but not for the subgroup without DSM diagnosis. Publication year was identified as a potential contributor to heterogeneity of the results from our analysis. Taken together, our findings support the notion that CBT influences peripheral IL-6 in individuals with depression and represents a point of commonality with other antidepressant treatment modalities (e.g., antidepressants). Systematic Review Registration https://doi.org/10.17605/osf.io/tr9yh , identifier: 10.17605/osf.io/tr9yh.
... Some researchers suggest that the cytokine profile might be specific for MDD subtype. Melancholic depression is supposed to be associated with a normalization of CRP during treatment, whereas other types of depression do not have such a relation (O'Brien et al., 2006;Rothermundt et al., 2001;Służewska et al., 1995). The response to treatment criterion is another distinction that we neglected to maximize the sample size. ...
Article
Introduction: Major Depressive Disorder (MDD) in accordance to the inflammatory concept is associated with complex immunological disturbances in the central nervous system (CNS). This is reflected by elevated plasma levels of inflammatory cytokines in depressed subjects. Although numerous studies report significant influence of antidepressants on pro-inflammatory/anti-inflammatory cytokines balance, the available data is often inconsistent regarding specific cytokines and drugs used. We aimed to perform a comprehensive meta-analysis of the effect of antidepressant treatment on a wide array of cytokines. Methods: We performed a systematic search of 6 databases, which yielded 32 studies measuring the levels of selected cytokines before and at a second time-point during antidepressant treatment. For meta-analysis of selected studies with a continuous measure we analysed variables containing the number of cases, mean and standard deviation of the level of IL-1ß, IL-2, IL-5, IL-6, IL-8, IL-10, CRP, TNF-α, IFN-γ levels observed in the different studies, in the intervention groups before and after antidepressant treatment. Results: Statistical analysis revealed significant decreases of IL-4, IL-6, and IL-10 in MDD subjects after antidepressant treatment. In case of IL-1ß the decrease was significant exclusively for SSRI drugs. We did not find any significant effect of antidepressant medication on IL-2, TNF-α IFN-γ and CRP. Conclusions: Antidepressant treatment affects the levels of cytokines in depression. The immunological imbalance in MDD is complex and seems to be mediated by other factors yet to be elucidated. The credibility of our results is limited by high heterogeneity among studies and very few studies with a placebo-controlled design. Research with MDD subtypes, response to treatment status and cytokine associations with the kynurenine pathway taken into account pose a promising target for future studies.
... In agreement with our results most reports of the literature found significantly higher baseline severity in melancholic subtype compared to non-melancholic patients (Kaestner et al., 2005;Khan et al., 2006;McGrath et al., 2008;Uher et al., 2011;Whiffen, Parker, Wilhelm, Mitchell, & Malhi, 2003), but not all (Fink et al., 2007;Rothermundt et al., 2001). Indeed, some authors suggested severity of depression as the only prerequisite of melancholic depression hypothesizing a threshold-model (Kendler, 1997;Schotte, Maes, Cluydts, & Cosyns, 1997), while others highlighted psychomotor disturbances as the most important and distinct core feature (Parker et al., 1995;Parker et al., 2000). ...
Article
Subtyping depression is important in order to further delineate biological causes of depressive syndromes. The aim of this study was to evaluate clinical and outcome characteristics of distinct subtypes of depression and to assess proportion and features of patients fulfilling criteria for more than one subtype. Melancholic, atypical and anxious subtypes of depression were assessed in a naturalistic sample of 833 inpatients using DSM-IV specifiers based on operationalized criteria. Baseline characteristics and outcome criteria at discharge were compared between distinct subtypes and their overlap. A substantial proportion of patients (16%) were classified with more than one subtype of depression, 28% were of the distinct anxious, 7% of the distinct atypical and 5% of the distinct melancholic subtype. Distinct melancholic patients had shortest duration of episode, highest baseline depression severity, but were more often early improvers; distinct anxious patients had higher NEO-Five Factor Inventory (NEO-FFI) neuroticism scores compared with patients with unspecific subtype. Melancholic patients with overlap of anxious features had worse treatment outcome compared to distinct melancholic and distinct anxious subtype. Distinct subtypes differed in only few variables and patients with overlap of depression subtypes may have independent clinical and outcome characteristics. Studies investigating biological causes of subtypes of depression should take influence of features of other subtypes into account.
... Ayrıca depresif epizodun tipi de bağışıklık sistemi yanıtını etkileyebilir. Melankolik tip MD olgularında INF γ (proinflamatuar etkili) ve IL-10 (antiinflamatuar etkili) düzeylerinin sağlıklı kontrol grubundan düşük olduğu, melankolik olmayan MD olgularının INF γ ve IL-10 düzeylerinin ise sağlıklı kontrol grubundan farklı olmadığı tespit edilmiştir (28). Bizim çalışmamızda ise atipik ve psikotik özellikli olgular dışlanmış fakat melankolik ve melankolik olmayan biçiminde bir ayrım yapılmamıştır. ...
Article
Amaç: Bu çalışmanın amacı major depresyon (MD) olgularında serum neopterin düzeylerinin tespiti suretiyle bağışıklık sisteminin aktivasyonunu incelemek ve tedavi öncesi serum neopterin düzeylerinin antidepresan tedaviye yanıtla ilişkisini araştırmaktır. Yöntem: Major depresyonu (n=30) olan hastalarda ve sağlıklı kontrol (n=26) deneklerinde tedavi öncesi serum neopterin düzeyleri ölçüldü. Major depresyonlu hastalara 8 hafta sertralin tedavisi uygulandı. Tedaviye cevap veren ve vermeyen major depresyon olgularının tedavi öncesi serum neopterin düzeyleri karşılaştırıldı. Bulgular: Major depresyon grubunun tedavi öncesi serum neopterin düzeyleri kontrol grubunun tedavi öncesi serum neopterin düzeylerinden daha yüksek bulundu. Tedaviye yanıt veren ve vermeyen major depresyon olgularının tedavi öncesi serum neopterin düzeyleri arasında fark bulunmadı. Sonuç: Major depresyonda serum neopterin düzeyini araştıran çalışmaların sonuçları çelişkilidir. Bu çalışmada major depresyon grubunda serum neopterin düzeyi kontrol grubundan yüksek bulunmuştur. Aynı zamanda sertralin tedavisine yanıt veren ve vermeyen grupların tedavi öncesi serum neopterin düzeylerinin farklı olmadığı saptanmıştır. Major depresyon hastalarında tedavi öncesi serum neopterin düzeylerinin yüksek oluşu, bağışıklık sisteminin bu hastalığın patofizyolojisinde bir rolü olabileceğini, fakat bu durumun tedaviye yanıtı belirlemede yararlı olamayacağını düşündürmektedir.
... On the other hand, it has been stated that potential mediators of inflammation markers, including leukocytes, neutrophils, complements, and C-reactive proteins increase in response to depression [53]. Previous studies have showed that patients with depression have reduced lymphocyte answers to mitogen stimulation and disorders in neutrophil activity [54][55][56]. In general, the findings of our study are consistent with those of previous studies, indicating increased neutrophil and leukocyte counts in adolescents with depression. ...
Article
Full-text available
OBJECTIVE: Neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), mean platelet volume (MPV), and red cell distribution width (RDW) were determined to be good indicators of inflammatory status. The aim of this study was to investigate NLR, PLR, MPV, and RDW, which can provide insight into diagnosis and/or prognosis in adolescents with major depressive disorder (MDD) compared to controls. METHOD: A total of 103 patients diagnosed with MDD, who received no antidepressant therapy within the past 1 month, were included in the study. The control group consisted of 41 healthy subjects with no organic and psychiatric disorders. RESULTS: NLR and MPV values were significantly high in adolescents with MDD compared with healthy controls (2.00 ± 0.80 vs. 1.63 ± 0.64, P = .011; 10.25 ± 0.91 vs. 9.62 ± 1.23, P = .005). There was no difference between the groups on PLR and RDW. There was a positive correlation between NLR and Children’s Depression Scale (CDI) scores in the total study group (r = 0.229, P = .006). There was also a positive correlation between MPV and CDI scores in the total study group (r = 0.185, P = .028). CONCLUSION: The findings of the study reveal that NLR and MPV tend to be higher in adolescents with MDD, and higher NLR values are associated with higher CDI scores in adolescents. The findings of this study are consistent with the relevant literature of inflammatory status in MDD. Our study gave us an idea of the need for larger sample study on the routine use of blood parameters in adolescent depression.
... 4 A decreased lymphocyte response to mitogen stimulation and disorders in neutrophil activity has been observed in depression. [29][30][31] In mice having undergone an olfactory bulbectomy and in various models of learned helplessness, neutrophil phagocytosis was indicated to be a sensory determinant of stress response. 32 The number, serum concentration and proliferation of lymphocytes, B-cells and T-cells decrease in MDD. ...
Article
Full-text available
Studies attempting to clarify the relationship between major depressive disorder (MDD) and the immune system have been increasing in recent years. It was reported that increased production of the main proinflammatory cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, and that of acute phase reactants may play a role in the etiopathogenesis of depression. Stress and depression were reported to increase leukocyte and neutrophil counts and to decrease lymphocyte count. Biological determinants affecting the diagnosis, therapy, and prognosis of depression are quite limited. Therefore, new etiological models are needed to explain the pathophysiology of depression. In recent years, neutrophil-lymphocyte ratio (NLR) was determined to be a good indicator of inflammatory status. There is no study in the literature investigating NLR in MDD. This study aims to examine the role of inflammation in the etiology of depression based on the NLR in MDD patients who are undergoing no pharmacological therapy. A total of 41 patients diagnosed with MDD, who received no antidepressant therapy within the past 1 month, were included in the study, which took place between January and March 2015. The control group consisted of 47 healthy subjects with no psychiatric disorders. A sociodemographic information form and a Beck Depression Scale were administered, and the blood was taken for biochemical analysis. Significant differences were identified in the NLR, neutrophil count, lymphocyte percentage, and leukocyte values of the patient group when compared with the control group (P<0.05). Our study is the first in which NLR was investigated in MDD. The findings of the study reveal that NLR tends to be higher in patients with MDD, and a high NLR value supports the view that inflammation is a critical factor in the etiology of MDD.
... BDI or physical activity level. [30][31][32][33] IL-1 RA has been found to be strongly elevated in people with obesity. 34) Accordingly the SFD group showed a significant correlation between BMI and both IL-6 and IL-1 RA. ...
Article
Full-text available
Objective: Previous studies have suggested alterations in the kynurenine pathway as a major link between cytokine and neurotransmitter abnormalities in psychiatric disorders. Most of these studies used a cross-sectional case-control study design. However, knowledge is still lacking regarding the stability over time of kynurenine pathway metabolites and the functionally related cytokines. Therefore, we studied the stability of cytokines and tryptophan (TRP) parameters over a period of 12 weeks. Methods: A total of 117 participants-39 with major depression, 27 with somatoform disorder, and 51 healthy controls were enrolled. Four evaluations, including blood withdrawal and psychometric testing, were performed over a period of 12 weeks. We used ELISA to measure interleukin (IL)-6, IL-1 receptor antagonist (RA) and tumor necrosis factor α (TNF α). High-performance liquid chromatography was used to analyze neurotransmitter variables, i.e. TRP, 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), 3-OH-kynurenine (3-HK), and kynurenic acid (KYNA). Results: We found no significant fluctuations of TRP, its metabolites (5-HIAA, KYN, KYNA, and 3-HK), or the cytokines (IL-1RA, IL-6, and TNF α) in any of the groups over the 12 weeks. Conclusion: To our knowledge, this is the first longitudinal study performed in psychiatric patients to verify the stability and consequently the reliability of the biological parameters we investigated. Our data indicate that TRP metabolites and cytokines are reliable biological parameters in psychiatric research because they do not fluctuate significantly over time.
... Furthermore, the literature indicates that only specific subtypes of depression are associated with inflammation. For example, patients with A c c e p t e d M a n u s c r i p t 5 atypical depression have an increase in plasma CRP (Hickman et al., 2014), proinflammatory cytokines (Lamers et al. 2013) and leukocyte numbers (Rothermundt et al., 2001) compared to healthy controls or patients with melancholic depression, although one report supports both melancholic and atypical patients having elevated biomarkers of inflammation (Karlovic et al., 2012). Interestingly, atypical depression is also characterized by symptoms of fatigue, hypersominia and lethargy (Gold & Chorousos, 2002), which match the known behavioral effects of cytokines. ...
Article
Full-text available
Inflammation and depression are closely inter-related to each other, inflammation inducing symptoms of depression and conversely depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission.
... Proteins may be good biomarkers, also because they are biologically more proximal to the disease phenotype, and they allow to study the ultimate product deriving from the stratification of environmental variables, as well as genetic, epigenetic, and post-transcriptional/translational modifications. To date, however, the identification of costeffective biomarker panels with good diagnostic performance is still an arduous and ambitious challenge, mostly due to the heterogeneous nature of depression and its complex etiology [7,10]. ...
Article
Full-text available
Depression affects 7% of the elderly population, and it often remains misdiagnosed or untreated. Peripheral biomarkers might aid clinicians by allowing more accurate and well-timed recognition of the disease. We sought to determine if plasma protein levels predict the severity of depressive symptomatology or distinguish patients from healthy individuals. The severity of depressive symptoms and global cognitive functioning were assessed by the Geriatric Depression Scale (GDS) and Mini-Mental State Examination (MMSE) in 152 elderly subjects, 76 of which with major depressive disorder (MDD). Plasma levels of 24 proteins were measured by multiplexing and analyzed as continuous predictors or dichotomized using the median value. The association between individual plasma proteins and MDD risk or depressive symptoms severity was investigated using multiple logistic and linear regressions including relevant covariates. Sensitivity analyses were performed excluding cognitively impaired individuals or non-acute patients with MDD. After adjusting for possible confounders and false discovery rate (FDR) correction, we found lower Fetuin-A levels in MDD patients vs. controls (pFDR = 1.95 × 10-6). This result was confirmed by the sensitivity and dichotomized analyses. Lower prolactin (PRL) levels predicted more severe depressive symptoms in acute MDD patients (pFDR = 0.024). Fetuin-A is a promising biomarker of MDD in the elderly as this protein was negatively associated with the disorder in our sample, regardless of the global cognitive functioning. Lower PRL levels may be a peripheral signature of impaired neuroprotective processes and serotoninergic neurotransmission in more severely depressed patients.
... Moreover, previous studies have indicated the effects of different inflammatory processes on different subtypes of depression (58)(59)(60). For example, non-melancholic patients exhibited the cytokine production of increased pro-inflammatory, whereas melancholic patients, in contrast, exhibited the cytokine production of reduced pro-inflammatory (61)(62)(63). The decline in IL-8 expression in the dorsolateral prefrontal cortex has been reported to be involved in the neurobiology of MDD suicides (39). ...
Article
Full-text available
Objective The interleukin-8 (IL-8) has been reported to play an important role in depression, which might be modulated by the selective serotonin reuptake inhibitors (SSRIs). Thus, the aim of this study was to investigate serum IL-8 levels, depressive symptom, and their associations in drug-free MDD patients, MDD patients with SSRIs, and healthy controls (HCs). Methods Fifty-seven drug-free MDD patients (male/female = 35/22, mean age: 39.24 years), 30 MDD patients with SSRIs (male/female = 11/19, mean age: 39.73 years), and 101 HCs (male/female = 52/49, mean age: 37.38 years) were recruited in this cross-sectional study. Serum IL-8 levels and depressive symptom were assessed using the Flow Cytometer and Hamilton Depression Scale (HAMD). The analysis of variance was used for the comparison between groups. The relationship between serum log 10 IL-8 levels and HAMD score was analyzed by Pearson correlation. Results Serum log 10 IL-8 levels were lower in all patients than HCs after controlling for covariates ( F = 4.86, p = 0.03). There was significant difference in serum Log 10 IL-8 levels among three groups after controlling for covariates ( F = 14.63, p < 0.001). Serum Log 10 IL-8 levels in drug-free patients were lower compared to HCs ( F = 19.38, p < 0.001) or patients with SSRIs ( F = 21.89, p < 0.001) after controlling for covariates. However, there was not difference in serum log 10 IL-8 levels between patients with SSRIs and HCs after controlling for covariates. Moreover, serum Log 10 IL-8 levels were negatively correlated with HAMD score in all patients ( r = −0.37, p = 0.02). Also, serum Log 10 IL-8 levels were negatively correlated with HAMD score in drug-free patients ( r = −0.74, p = 0.01), but not in patients with SSRIs. Conclusion Our data supported that the decline in serum IL-8 levels was association with depression. Moreover, the SSRIs might modulate increased serum IL-8 levels of depression.
... We suspect that the inconsistency in the results may have arisen due to sample differences including the number of MDD attacks, the proportion of melancholic MDD, and different stages of MDD, for example. In addition, it is unclear that whether immune response, neuroplasticity, or other factors contributed to the failure to replicate genetic effects of DVL3 gene in the CONVERGE sample [36][37][38][39][40][41]. ...
Article
Full-text available
Based on the “oxidative stress hypothesis” of major depressive disorder (MDD), cells regulate their structure through the Wnt pathway. Little is known regarding the interactions of dishevelled 3 (DVL3) and glycogen synthase kinase 3 beta (GSK3β) polymorphisms with MDD. The aim of the current study was to verify the relationship between DVL3 and GSK3β genetic variants in a Chinese Han population and further to evaluate whether these interactions exhibit gender-specificity. A total of 1136 participants, consisting of 541 MDD patients and 595 healthy subjects, were recruited. Five single-nucleotide polymorphisms (SNPs) of DVL3/GSK3β were selected to assess their interaction by use of a generalized multifactor dimensionality reduction method. The genotype and haplotype frequencies of DVL3/GSK3β polymorphisms were significantly different between patients and controls for DVL3 rs1709642 ( P < 0.01 ) and GSK3β rs334558, rs6438552, and rs2199503 ( P < 0.01 ). In addition, our results also showed that there were significant interaction effects between DVL3 and GSK3β polymorphisms and the risk of developing MDD, particularly in women. The interaction between DVL3 (rs1709642) and GSK3β (rs334558, rs6438552) showed a cross-validation (CV) consistency of 10/10, a P value of 0.001, and a testing accuracy of 59.22%, which was considered as the best generalized multifactor dimensionality reduction (GMDR) model. This study reveals the interaction between DVL3 and GSK3β polymorphisms on MDD susceptibility in a female Chinese Han population. The effect of gender should be taken into account in future studies that seek to explore the genetic predisposition to MDD relative to the DVL3 and GSK3β genes.
... Enhanced noradrenergic signalling and decreased serotonin activity may lower the production of Th1 cytokines (IL-2, IFN-γ), causing a Th2 shift [161]. This is consistent with previous observations of higher levels of IL-4 versus lower levels of IL-2 and IFN-γ in melancholic depression (characterised by typical neurovegetative symptoms amongst other symptoms) [162,163]. A chronic hypernoradrenergic state may also drive the increase in systemic IL-6 levels, since norepinephrine upregulates IL-6 production [156]. ...
Article
Depression onset peaks during adolescence and young adulthood. Current treatments are only moderately effective, driving the search for novel pathophysiological mechanisms underlying youth depression. Inflammatory dysregulation has been shown in adults with depression, however, less is known about inflammation in youth depression. This systematic review identified 109 studies examining the association between inflammation and youth depression and showed subtle evidence for inflammatory dysregulation in youth depression. Longitudinal studies support the bidirectional association between inflammation and depression in youth. We hypothesise multiple inflammatory pathways contributing to depression. More research is needed on anti-inflammatory treatments, potentially tailored to individual symptom profiles.
... Serum Hp ve MD arasındaki ilişkiyi inceleyen çalışmalarda daha çok depresyon hastaları ile kontrol grupları ve melankolik ve melankolik olmayan MD grupları arasındaki ilişki ince- lenmiştir. Karşıt bulguların olduğu çalışmalar da olmakla birlikte(35,36,38), melankolik MD hastalarında melanko- lik olmayan MD hastalarına ve kontrol grubuna göre yük- selmiş serum Hp seviyeleri bulunmuştur(20). Bazı çalış- malarda, immün sistemdeki değişikliklerin MD hastala- rında depresyon şiddeti ile ilişkili olabileceği gösterilmiş- tir(36,39,40). ...
Article
Full-text available
In explaining the association between depression and immune system pro-inflammatory cytokines have come to the fore and there appears to be an increase in particular at the cellular immune response. Neopterin measurements enable monitoring of the cellular immune response although its specific function is still not fully described. Similarly, haptoglobin (Hp), a positive acute phase protein, has been mentioned as well. In this study, we aimed to investigate the effects of depressive episodes on serum levels of neopterin and Hp by comparing serum haptoglobin and neopterin levels of the depressive patients in their first attack with those of depression patients suffering from recurrent attacks, and with the healthy control group. Method: Eighty patients who admitted to the outpatient psychiatry clinic of Ankara Gulhane Military Medical Academy (GMMF) were included in the study. Fourty-four individuals were being followed up with a diagnosis of first episode depression. There were 36 patients in the recurrent major depression (MD) group. The control group consisted of 41 healthy individuals. Of recurrent MD patients, 22 patients were in their second episode, 16 patients were in their third attack and 6 patients had four episodes or more. Severity of depression was evaluated with 17-item Hamilton Depression Rating Scale (HAM-D). Peripheral venous blood samples were collected from participants to determine complete blood count, routine biochemistry, serum neopterin, and haptoglobin measurements. The levels of serum neopterin and haptoglobin were measured by using the samples that were collected between the hours of 8:00 am and 11:00 am after 12 hour fasting during the previous night. Results: There was no significant difference between the three groups in terms of gender, age, educational level, and smoking. There was also not significant difference between the first episode MD and recurrent MD groups for HAM-D scores. No significance was detected between the first episode MD and control groups in terms of serum Hp and neopterin levels. In the recurrent MD group serum Hp and neopterin levels were higher than those of the first episode MD patients and the control subjects. HAM-D scores of MD patients (both first-episode MD and recurrent MD group) were correlated with serum levels of Hp, but there was no correlation between serum neopterin levels and HAM-D scores. Conclusion: The independent factor affecting the neopterin and Hp levels in patients with MD was found as the number of episodes of depression. Recurrent episodes have resulted with increased levels of both markers. We believe that this finding is important. Our findings support the hypothesis that major depressive disorder is generally associated with widespread inflammatory reaction and severity of depressive symptoms are positively correlated with the increase in inflammatory markers. Serum levels of Hp were associated with depression severity in patients who had a single episode as well as patients with multiple episodes. The same relationship was not found for neopterin. Further studies are needed to determine the importance of this difference observed between the two markers and also etiological significance of them.
... HPA hyperactivation and sustained cortisol elevation have repeatedly been indicated as distinct features of melancholic depression which can differentiate it from atypical depression [230,424,425]. Melancholic depression is characterized by a lower absolute monocyte count, increased haptoglobin, IL-6 and CRP, enhanced expression of T cell activation markers, and increased resistance of sIL-2R and IL-1β production in response to dexamethasone administration as compared to non-melancholic depression [426][427][428][429][430][431]. Higher triglycerides and fatty acids have been observed in the melancholic subtype [366]. ...
Article
Full-text available
Major Depressive Disorder (MDD) is a leading cause of disability worldwide, creating a high medical and socioeconomic burden. There is a growing interest in the biological underpinnings of depression, which are reflected by altered levels of biological markers. Among others, enhanced inflammation has been reported in MDD, as reflected by increased concentrations of inflammatory markers—C-reactive protein, interleukin-6, tumor necrosis factor-α and soluble interleukin-2 receptor. Oxidative and nitrosative stress also plays a role in the pathophysiology of MDD. Notably, increased levels of lipid peroxidation markers are characteristic of MDD. Dysregulation of the stress axis, along with increased cortisol levels, have also been reported in MDD. Alterations in growth factors, with a significant decrease in brain-derived neurotrophic factor and an increase in fibroblast growth factor-2 and insulin-like growth factor-1 concentrations have also been found in MDD. Finally, kynurenine metabolites, increased glutamate and decreased total cholesterol also hold promise as reliable biomarkers for MDD. Research in the field of MDD biomarkers is hindered by insufficient understanding of MDD etiopathogenesis, substantial heterogeneity of the disorder, common co-morbidities and low specificity of biomarkers. The construction of biomarker panels and their evaluation with use of new technologies may have the potential to overcome the above mentioned obstacles.
... On the other hand, Karlović et al. mentioned that there was no difference between melancholic and atypical depression cases regarding CRP level [19] and also, Bai et al. noted that no CRP difference was found between atypical, melancholic, and unspecified groups [20]. In addition, another study conducted by Rothermundt et al. in which no difference was found between nonmelancholic depression and melancholic cases as regard CRP level [21]. Other studies observed that there was no difference in the levels of inflammatory cytokines between MDD subtypes [22,23]. ...
Article
Full-text available
Background Although, the relation between inflammation and major depressive disorder (MDD) looks like firm, it may not exist in all patients with depression. Therefore, the main aim of this study was to compare serum C-reactive protein (CRP) level among clinical subtypes of MDD and its relation with suicidality. Results According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD, 98 patients included and categorized into five clinical subtypes groups: atypical, anxious, melancholic, psychotic, and unspecified depression with percent (11.2%, 31.6%, 19.4%, 15.3%, and 22.4%) respectively. Twenty-four (24.5%) of all patients had suicidal thoughts using Beck Scale for Suicidal Ideation (BSS) with statistically significant increase ( P < 0.05*) in suicidality among atypical group. On assessing CRP level, there was highly statistical significant increase ( P < 0.001**) among cases with atypical type and also cases with suicidal ideation. Also, logistic regression analysis found that the significant predictors for high CRP among the studied cases were smoking, suicidality, atypical depression, and suicide depression. Conclusions Higher level of CRP was found among patients with atypical MDD, and there was significant relationship between CRP and suicidality.
... It is also plausible that different inflammatory profiles are associated with different subtypes of depression (Dunjic-Kostic et al., 2013;Kaestner et al., 2005;Karlovi c et al., 2012). Thus, nonmelancholic patients exhibit proinflammatory states, whereas melancholic patients, in contrast, exhibit reduced proinflammatory cytokine production (for review, see Kronfol, 2002;Rothermundt et al., 2001a;Rothermundt et al., 2001b). In addition, TNF has been associated with atypical features and chronicity, ...
Article
Depression represents the number one cause of disability worldwide and is often fatal. Inflammatory processes have been implicated in the pathophysiology of depression. It is now well established that dysregulation of both the innate and adaptive immune systems occur in depressed patients and hinder favorable prognosis, including antidepressant responses. In this review, we describe how the immune system regulates mood and the potential causes of the dysregulated inflammatory responses in depressed patients. However, the proportion of never-treated major depressive disorder (MDD) patients who exhibit inflammation remains to be clarified, as the heterogeneity in inflammation findings may stem in part from examining MDD patients with varied interventions. Inflammation is likely a critical disease modifier, promoting susceptibility to depression. Controlling inflammation might provide an overall therapeutic benefit, regardless of whether it is secondary to early life trauma, a more acute stress response, microbiome alterations, a genetic diathesis, or a combination of these and other factors.
... Life isn't going well for me right now" … Sadness is characteristic of depression, but lack of happiness is even more characteristic. (Kalat, 2011, p. 590, p. 590) Several studies have linked the notion of melancholy with depression, as in the case of melancholic depression (Hill & Gorzalka, 2005;Khan et al., 2006;Weinberg, 2016;Winograd-Gurvich et al., 2006), melancholic major depression (Rothermundt et al., 2001), and pharmacotherapy for major depression with melancholic features (Perry, 1996). Nonetheless, certain researchers have agreed that "melancholia" in ancient times and during the seventeenth and eighteenth centuries seems to have meant what "depression" means today (Blazer, 2005;Ioannidou, 2005). ...
Article
Although it cannot be interpreted as severe depression, melancholy has disquieted individuals and societies for millennia. This study explores the extent to which tourism can move beyond the formation of enjoyable experiences and become a source of comfort for melancholy. The present study reveals that tourism does not act as a panacea for melancholy. Nonetheless, it may substantially relieve the symptoms through a concurrent amalgam of pleasure and activity factors, distractions, and the seclusion choices it offers. The eagerness associated with an imminent leisure trip and the strength to fight challenges in the personal and social domains following a reviving travel experience are also imperative comforting dynamics. A relevant research agenda is proposed, and the managerial implications for how the tourism industry can secure comforting experiences are discussed.
... Several studies explore the effects of SSRIs on adaptive immune cells [35,[49][50][51]. Early studies in this area explored the effect of SSRIs for 4-12 weeks in MDD patients and noted a main finding -SSRIs decrease the number of circulating NK cells without affecting other lymphocyte subsets [52][53][54][55]. Increased counts of NK cells might occur due to stimulation of their serotonergic receptors as the result of increased levels of 5-HT caused by long-term SSRI treatment [51]. ...
Article
Current reviews exploring for unique immune-modulatory profiles of antidepressant classes are limited by focusing mainly on cytokine modulation only and neglecting other aspects of the innate and adaptive immune system. These reviews also do not include recent comparative clinical trials, immune-genetic studies and therapeutics with unique neurotransmitter profiles (e. g., agomelatine). This systematic review extends the established literature by comprehensively reviewing the effects of antidepressants classes on both the innate and adaptive immune system. Antidepressants appear, in general, to reduce pro-inflammatory factor levels, particularly C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. We caution against conclusions as to which antidepressant possesses the greater anti-inflammatory effect, given the methodological heterogeneity among studies and the small number of comparative studies. The effects of antidepressant classes on adaptive immune factors are complex and poorly understood, and few studies have been conducted. Methodological heterogeneity is high among these studies (e. g., length of study, cohort characteristics, dosage used and immune marker analysis). We recommend larger, comparative studies - in clinical and pre-clinical populations. © Georg Thieme Verlag KG Stuttgart · New York.
Thesis
Full-text available
Resumo: A depressão é um transtorno psiquiátrico altamente prevalente e oneroso, sendo uma das principais causas mundiais de morbimortalidade. Contudo, seu status nosológico é tema de profundas controvérsias, uma vez que apresenta uma definição pouco precisa, gerando uma enorme heterogeneidade clínica. Esta tese é composta por quatro artigos, e visa estudar a heterogeneidade da depressão investigando suas interações com o construto de personalidade e com marcadores biológicos. Os dois primeiros artigos visam viabilizar o uso de um instrumento de avaliação de estilos de personalidade, o Temperament and Personality Questionnaire (T&P). O primeiro artigo descreve o processo de tradução e adaptação transcultural do T&P para o português brasileiro, utilizando uma metodologia estandardizada. O segundo artigo examina as propriedades psicométricas do T&P em uma amostra de pacientes deprimidos. Nesse artigo, análises fatoriais confirmatórias foram realizadas para testar os sete níveis do instrumento, sendo encontrados índices de ajuste adequados para modelos com dois até quatro fatores, com alta consistência interna para todos os níveis. Foram encontradas as associações esperadas entre os estilos de personalidade e dois validadores externos, com estilos de personalidade resilientes apresentando menor qualidade de vida e maiores níveis de depressão, enquanto estilos de personalidade desordenados apresentaram o inverso. Além disso, a performance dos itens foi explorada utilizando a Teoria de Resposta ao Item, com a maioria dos itens apresentando melhor padrão de respostas dicotômico. Por fim, correlações altas entre os estilos de personalidade de níveis de baixa ordem com seus correspondentes construtos molares, confirmaram a organização hierárquica do instrumento. O terceiro artigo estudou a heterogeneidade da depressão em relação a personalidade. Nele, foi avaliada a associação entre dimensões depressivas (definidas por análise fatorial exploratória) e quatro classes de personalidade (criadas a partir de uma análise de classes latentes) em uma amostra de pacientes deprimidos. As classes de personalidade foram denominadas resilientes e desordenadas de acordo com seu nível de funcionamento e qualidade de vida. A classes desordenadas apresentaram maiores escores de sintomatologia depressiva, principalmente na dimensão cognitiva, com maior comorbidade com transtornos ansiosos. As dimensões depressivas melancólicas foram pouco ou nada discriminativas em relação às classes de personalidade, reforçando sua maior relevância para as depressões não-melancólicas. O quarto artigo analisou subgrupos depressivos classificados por um instrumento de avaliação de alterações da psicomotricidade (o CORE). Os grupos melancólico e não-melancólico foram comparados em relação a três dimensões de marcadores biológicos (estresse oxidativo, neurotrofina e marcadores imunológicos). Os resultados replicaram e estenderam achados sobre diferenças biológicas de subtipos depressivos, mostrando a importância da avaliação dos sinais de melancolia. Assim, essa tese contribui no estudo da heterogeneidade da depressão viabilizando o uso de um instrumento de avaliação da personalidade e estendendo achados que podem possibilitar que subtipos depressivos possam ser avaliados em relação a estilos de personalidade e marcadores biológicos. Abstract: Depression is a highly prevalent and burdensome psychiatric disorder, and one of the main causes of morbidity and mortality. However, its nosological status remains the subject of deep controversies, since it presents an imprecise definition, generating an enormous clinical heterogeneity. This thesis comprises four papers, and aims to study the heterogeneity of depression investigating its interactions with the construct of personality and with biologic markers. The first two papers aim to enable the use of an instrument for assessing personality styles, the Temperament and Personality Questionnaire (T&P). The first paper describes the process of translation and cross-cultural adaptation of the T&P into Brazilian Portuguese using standardized methodology. The second paper examines the psychometric properties of the T&P in a sample of depressed patients. In this paper, confirmatory factor analyzes were conducted in order to test the seven tiers of the instrument, with proper goodness fit for models from two to four factors, and high internal consistency for all levels. The expected associations between personality styles and two external validators (quality of life and depression) were found, with resilient personality styles presenting lower quality of life and higher levels of depression, while disordered personality styles showed the reverse. Moreover, the performance of the items was explored using the Item Response Theory, and most items showed a better dichotomous response pattern. Finally, high correlations between lower-order personality styles and their corresponding molar personality constructs were found, confirming the hierarchical organization of the instrument. The third paper studied the heterogeneity of depression in relation to personality. In it, the association 14 between depressive dimensions (defined by exploratory factor analysis) and four personality classes (created by latent class analysis) was evaluated in a sample of depressed patients. Classes were named resilient and disordered according to their level of functioning and quality of life. The disordered classes had higher scores of depressive symptoms, especially in the cognitive dimension, and higher comorbidity with anxiety disorders. The melancholic depressive dimensions were little or no discriminative with respect to the personality classes, reinforcing its greater relevance to non-melancholic depression. The fourth paper examined depressive subgroups classified by an assessment instrument of psychomotor changes (the CORE). The melancholic and non-melancholic groups were compared with respect to three dimensions of biomarkers (oxidative stress, neurotrophin and immunological markers). Results replicated and have extended findings on biological differences in depressive subtypes, showing the importance of evaluating signs of melancholia. Thus, this thesis contributes to the study of depression heterogeneity enabling the use of an instrument for assessing personality and extending findings that may allow that depressive subtypes can be assessed in relation to personality styles and biological markers.
Article
Emil Kraepelin, the founder of modern psychiatric classification, and the Nobel laureate Julius Wagner von Jauregg highlighted the role of infections and the immune system in psychiatric disorders. It is well known that infections can trigger various psychiatric syndromes and influence the course of psychiatric disorders. Psychiatric symptoms during virulent infections, often presenting as encephalitis or meningitis, normally are diagnosed as mental disorders due to a general medical condition. On the other hand, an expanding research field underpins the view that infections and activation of the immune system may play a causative role in major psychiatric disorders such as schizophrenia or major depression. Also in other psychiatric syndromes, such as Tourette's syndrome, inflammation-partially based on infections-is involved. For this mild smoldering inflammatory process, the 'mild (chronic) encephalitis' concept was developed. In this chapter, findings related to immune activation and inflammation in schizophrenia, major depression and Tourette's syndromes as examples for this concept are described. Moreover, encouraging results from randomized clinical trials in schizophrenia and major depression showing a benefit of anti-inflammatory therapy in these psychiatric disorders are discussed as examples for immunomodulating treatment approaches in psychiatric disorders. Further immunotherapies used in Tourette's syndrome or pediatric autoimmune disorders associated with streptococci are highlighted as further examples for such a therapeutic approach.
Article
Major depression is a highly prevalent mood disorder associated with reduced psychological and physical functioning that, despite its apparently detrimental symptoms, has not been eliminated by natural selection. Several evolutionary hypotheses explain this seemingly paradoxical fact by suggesting that depression is an adaptation. Most hypotheses, such as the analytical rumination, social navigation and social risk hypothesis, focus on beneficial social properties: Depressive behavior might focus the individual on solving complex social problems, elicit social support, or avoid social risks. The infection–defense hypothesis proposes a different view, according to which depression serves to fight and prevent infections. This ultimate account of depression can be supported by the cytokine hypothesis of depression, which supplements it with a proximate mechanism: Cytokines are messengers of the immune system that can induce depressive symptoms. The discussed evolutionary hypotheses offer plausible explanations, but at the same time, cannot arguably explain all complexities of the disorder alone. However, a combination of these hypotheses might prove to be the most convincing explanation of depression’s evolutionary roots.
Article
Full-text available
Accession Number: 86653728; Bolu, Abdullah 1; Email Address: abdullah_bolu@yahoo.com Erdem, Murat 1 Balıkcı, Adem 1 Emrah Bilgen, Ali 1 Özgür Akgül, Emin 2 Uzun, Özcan 1 Öztosun, Muzaffer 3; Affiliation: 1: MD, GATA Ruh Sağlığı ve Hastalıkları Anabilim Dalı, Ankara-Türkiye 2: GATA Biyokimya Anabilim Dalı, Ankara - Türkiye 3: TSK Sağlık Komutanlığı Sağlık Hizmetleri, Ankara-Türkiye; Source Info: 2013, Vol. 3 Issue 1, p1; Subject Term: SERUM; Subject Term: BLOOD proteins; Subject Term: HAPTOGLOBINS; Subject Term: NEOPTERIN; Subject Term: MENTAL depression -- Treatment; Subject Term: DEPRESSED persons; Subject Term: MEDICAL care; Subject Term: PHYSIOLOGICAL aspects; Subject Term: THERAPEUTIC use; Author-Supplied Keyword: depression; Author-Supplied Keyword: haptoglobins; Author-Supplied Keyword: neopterin; Author-Supplied Keyword: depresyon; Author-Supplied Keyword: haptoglobinler; Author-Supplied Keyword: neopterin; Language of Keywords: English; Language of Keywords: Turkish;
Article
Objective: The aim of this study was to examine the activity of immune system in patients with major depression by using serum neopterin levels as a biochemical tool. Also, this study aimed to illuminate the relationships between pretreatment serum neopterin levels and clinical responses to antidepressant treatment. Method: Pretreatment serum neopterin levels were measured in patients with major depression (n=30) and in healthy controls (n=26). Patients with major depression were given sertraline for 8 weeks. In the major depression patients who response to the treatment or not, pretreatment serum neopterin levels were compared. Results: The serum neopterin levels of major depression group were higher than the serum neopterin levels of control group. The pretreatment serum neopterin levels in the major depression patients who respond to the treatment or not could not be found any difference. Conclusions: The results of the studies that investigate the serum neopterin levels in major depression were conflict. In this study the serum neopterin levels in major depression group was found higher than the serum neopterin levels of the control groups. Also it was determined that there was no difference between respond to the sertraline treatment group and not respond to the sertraline treatment group. The finding pretreatment serum neopterin levels were higher in the patients with major depression suggests that immune system might play a role in the pathophysiology of this disorder, but this finding is not suitable for the predicting of the treatment.
Article
Depression and inflammatory markers have a reliable cross-sectional association although less is known about the prospective relationship. The current study investigated whether pro-inflammatory markers are prospectively associated with depression, and whether indicators of unhealthy lifestyle, physical health and psychosocial functioning may drive this association. Participants were drawn from the Hunter Community Study, a community-dwelling cohort of individuals aged 55-85 years (N = 1410). Participants completed baseline physiological assessment, health-related questionnaires, and blood sampling for the analysis of inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6. Participants completed the same depressive symptom questionnaire again after 3.5-5.5 years. Depression outcomes at follow-up were analysed dichotomously using established scale cut-off scores and continuously as a "residual score", representing the variation in follow-up depressive symptoms not explained by baseline symptoms and age. Analyses were conducted on males and females separately. At baseline, indicators of unhealthy lifestyle, physical health and psychosocial functioning were associated with depressive symptoms and inflammatory markers. For males, there were no relationships between inflammatory markers and follow-up depression outcomes. In females, IL-6 was significantly associated with depression outcomes in univariate, but not multivariate analyses. However, IL-6 significantly mediated the association between the predictors of waist-to-hip ratio, smoking and psychological coping at baseline, and follow-up depression outcomes. The results support the inflammatory hypothesis of depression, although females may be more vulnerable to effects. The findings raise the possibility that unhealthy lifestyle and psychosocial stress may drive inflammation and subsequent depressive symptoms. Copyright © 2015 Elsevier Ltd. All rights reserved.
Chapter
Es bestehen vielfältige psychologische und biologische Verbindungen zwischen körperlichen Erkrankungen und unterschiedlichen depressiven Syndromen. Die psychische Bewältigung von körperlichen Erkrankungen und die Beteiligung psychischer Faktoren an ihrer Pathogenese stellen Fragestellungen dar, die in Deutschland bisher überwiegend im Bereich der Psychosomatik und der Medizinpsychologie bearbeitet wurden. Erst seit einigen Jahren wird die Verbindungslinie zwischen psychischer Störung und körperlicher Erkrankung zum Gegenstand intensiverer Forschungstätigkeit, wobei neben versorgungsepidemiologischen zunehmend (neuro-)biologische Fragestellungen fokussiert werden.
Chapter
High levels of several proinflammatory components of the immune system such as interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), or neopterin in patients suffering from major depression (MD) point to the involvement of an inflammatory process in the pathophysiology of MD. Direct and indirect effects of cytokines on the neurotransmitter storage and release—mediated by microglia cells and astrocytes—are discussed. The tryptophan/kynurenine metabolism mediates the activity of the immune system and the serotonergic and glutamatergic neurotransmissions. The enzyme indoleamine 2,3-dioxygenase (IDO)—a key enzyme of this metabolism in the central nervous system (CNS)—is driven by pro- and anti-inflammatory cytokines and degrades serotonin. Moreover, neuroactive kynurenines such as kynurenic acid and quinolinic acid act on the glutamatergic neurotransmission as N-methyl-d-aspartate (NMDA)—antagonists and agonists, respectively. Alterations of the serotonergic, noradrenergic, and glutamatergic neurotransmissions are associated with low-level neuroinflammation. Epidemiological and clinical studies point to a key role for inflammation as risk factor for MD. A large-scale epidemiological study in MD clearly demonstrates that severe infections and autoimmune disorders are lifetime risk factors for MD. Neuroinflammation in the prefrontal cortex, the nucleus accumbens, and the insula has been shown in MD by in vivo positron emission tomography. Further support comes from the therapeutic benefit of anti-inflammatory compounds in MD such as the cyclo-oxygenase-2 (COX-2) inhibitors or TNF-α antagonists. On the other hand, antidepressants have anti-inflammatory and immunomodulatory intrinsic effects. The beneficial effect of both, COX-2 inhibitors alone and of the approach of anti-inflammatory treatment in MD, has been shown in meta-analyses in the meantime.
Chapter
The clinical relationship between mental disorders and cardiovascular disease and risk factors is highly important with serious consequences for morbidity and mortality. A key biological mechanism in this complex and bidirectional relationship is related to immune dysregulation and inflammation in particular. This review critically evaluates the existing literature on the bidirectional nature of this relationship, the contributing clinical factors, and the role of inflammation in prevalent risk factors for both mental disorders and cardiovascular disease including obesity, endothelial dysfunction, and diabetes mellitus type 2. This chapter outlines the lines of biological mechanisms in the bidirectional relationship between mental disorders and cardiovascular disease by exemplifying this using depression as a common disorder. This focus on the role of immune dysregulation and inflammation in these risk factors and comorbid disease suggests new avenues for identifying and possibly treating early patients at risk, but also it opens up novel and preventive treatments such as the use of anti-inflammatories for both types of conditions.
Article
Background: Immune system dysfunction is implicated in the pathophysiology of major depression, and is hypothesized to normalize with successful treatment. We aimed to investigate immune dysfunction in melancholic depression and its response to ECT. Methods: 55 melancholic depressed patients and 26 controls participated. 33 patients (60%) were referred for ECT. Blood samples were taken at baseline, one hour after the first ECT session, and 48h after ECT series completion. Results: At baseline, melancholic depressed patients had significantly higher levels of the pro-inflammatory cytokine IL-6, and lower levels of the regulatory cytokine TGF-β than controls. A significant surge in IL-6 levels was observed one hour after the first ECT session, but neither IL-6 nor TGF-β levels normalized after completion of ECT series. Seventy per cent (n=23) of ECT recipients showed clinical response and 42% (n=10) reached remission. Neither IL-6 nor TGF-β changes correlated with clinical improvement following ECT. No significant changes in IL-10, TNF-α and CRP levels were found in relation to melancholia or response to ECT. Limitations: As a naturalistic study, some potential confounders could not be eliminated or controlled, including medication use. Conclusions: Melancholic depressed patients demonstrated a peripheral increase in IL-6 and reduction in TGF-β, which did not normalize despite clinical response to ECT. These findings may be consistent with emerging hypotheses of the role of inflammation in mediating neurotrophin expression. The implications of chronic inflammation in the melancholic depressed population for future medical health, particularly cardiovascular risk, are largely unknown and warrant further investigation.
Chapter
Psychische Erkrankungen weisen eine komplexe Pathophysiologie auf, die bis heute nur ansatzweise geklärt ist. Neben Veränderungen von Neurotransmittersystemen und Rezeptoren als deren Effektorsysteme, die dann auf nachgeschaltete Signaltransduktionsprozesse einwirken, mehren sich Hinweise, dass immunologische Mechanismen eine wichtige Rolle in der Pathophysiologie psychischer Erkrankungen spielen. Mittlerweile gibt es auch erste Ansätze, die versuchen, derartige Mechanismen im Sinne von neuartigen Therapiestrategien nutzbar zu machen.
Chapter
There has been great interest in the role of inflammation in psychiatric disorders of children and adolescents. This chapter begins by describing the normal development of the immune system from fetal life and earlier through infancy, childhood, and beyond. The role of genetics, environmental stressors, and trauma will be described and the sequelae that may follow. A focus will be the transition from normal to altered immunity and how that may later be expressed in the child. Links between inflammation and mood disorders are well documented, as are those associated with psychotic disorders. The latter group has been of interest for decades with the description of schizophrenia associated with infection. This chapter will trace earlier findings as they have evolved in the more recent past with technologically advanced evidence. Post-traumatic stress disorder (PTSD), increasingly more important for mental health professionals to understand, has diverse links to the immune system. Autism spectrum disorder (ASD) is another exciting area with multiple associations to inflammation and obsessive compulsive spectrum disorders have multiple alterations of interleukins. New evidence points to immune changes in children with attention deficit hyperactive disorder, as well as those with disruptive behavior. Critical to the complete understanding of suicide are the new reports of the neuroimmune system of suicidal patients. The chapter concludes with prominent bio-markers that have been identified in recent literature having connections with child and adolescent psychopathology. Current evidence points researchers toward an exciting new frontier that may offer new and more effective treatments in the future.
Article
BACKGROUND Given the well known heterogeneity of Major Depressive Disorder (MDD), dividing this complex disorder into subtypes is likely to be a more promising approach to identify its determinants than to study it as a whole. METHODS In a prospective population-based cohort study (CoLaus|PsyCoLaus) with 5.5 years of follow-up, 1524 participants without MDD at baseline, aged 35 to 66 years (mean age 51.4 years, 43.4% females), participated in the physical and psychiatric baseline and the psychiatric follow-up evaluations. RESULTS The incidence of both atypical and melancholic MDD during the follow-up period were predicted by female sex, a lifetime history of minor depressive disorders and higher neuroticism scores. Higher baseline body mass index was associated with the onset of atypical MDD, whereas the absence of hypertension and younger age were associated with the development of melancholic MDD. Unspecified MDD was predicted by younger age, low concentrations of tumor necrosis factor alpha and elevated life-event impact scores. LIMITATIONS The age range of our cohort restricts the identification of risk factors to MDD with onset in midlife and the recruitment in an urban area limits the generalizability of the findings. CONCLUSIONS Our data suggest that MDD subtypes are predicted by partially distinct combinations of baseline characteristics suggesting that these subtypes not only differ in their clinical manifestations but also in factors that contribute to their development. Subjects with minor depressive episodes, especially in combination with particular personality features, deserve close clinical attention to prevent the subsequent onset of atypical and melancholic major depression.
Article
Full-text available
The prevalence of depression worldwide is increasing from year to year and constitutes a serious medical, economic and social problem. Currently, despite multifactorial risk factors and pathways contributing to depression development, a significant aspect is attributed to the inflammatory process. Cytokines are considered a factor activating the kynurenine pathway, which leads to the exhaustion of tryptophan in the tryptophan catabolite (TRYCAT) pathway. This results in the activation of potentially neuroprogressive processes and also affects the metabolism of many neurotransmitters. The immune system plays a coordinating role in mediating inflammatory process. Beginning from foetal life, dendritic cells have the ability to react to bacterial and viral antigens, stimulating T lymphocytes in a similar way to adult cells. Cytotoxicity in the prenatal period shapes the predisposition to the development of depression in adult life. Allostasis, i.e. the ability to maintain the body's balance in the face of environmental adversity through changes in its behaviour or physiology, allows the organism to survive but its consequences may be unfavourable if it lasts too long. As a result, Th lymphocytes, in particular T helper 17 cells, which play a central role in the immunity of the whole body, contribute to the development of both autoimmune diseases and psychiatric disorders including depression, as well as have an impact on the differentiation of T CD4+ cells into Th17 cells in the later development of the child's organism, which confirms the importance of the foetal period for the progression of depressive disorders.
Article
Depression is a major mental health condition and is expected be the most debilitating and widespread health disorder by 2030. Tuberculosis (TB) is also a leading cause of morbidity and mortality worldwide and interestingly, is a common comorbidity of depression. As such, much attention has been paid to the association between these 2 pathologies. Based on clinical reports, the association between TB and depression seems to be bidirectional, with a substantial overlap in symptoms between the 2 conditions. TB infection or reactivation may precipitate depression, likely as a consequence of the host's inflammatory response and/or dysregulation of the hypothalamic–pituitary–adrenal axis. Nevertheless, few studies have considered whether patients with depression are at a higher risk for TB. In this review, we discuss the hypotheses on the association between depression and TB, highlighting the immuno‐inflammatory response and lipid metabolism as potential mechanisms. Improving our understanding of the interplay between these 2 disorders should help guide TB clinical care and prevention both in patients with comorbid depression and in the general population. Review on the association between depression and tuberculosis, includes a potential mechanism underlying depression's role in increasing the risk for tuberculosis.
Article
Background Mood disorders (major depressive disorder, MDD, and bipolar disorder, BD) are considered leading causes of life-long disability worldwide, where high rates of no response to treatment or relapse and delays in receiving a proper diagnosis (~60% of depressed BD patients are initially misdiagnosed as MDD) contribute to a growing personal and socio-economic burden. The immune system may represent a new target to develop novel diagnostic and therapeutic procedures but reliable biomarkers still need to be found. Methods In our study we predicted the differential diagnosis of mood disorders by considering the plasma levels of 54 cytokines, chemokines and growth factors of 81 BD and 127 MDD depressed patients. Clinical diagnoses were predicted also against 32 healthy controls. Elastic net models, including 5000 non-parametric bootstrapping procedure and inner and outer 10-fold nested cross-validation were performed in order to identify the signatures for the disorders. Results Results showed that the immune-inflammatory signature classifies the two disorders with a high accuracy (AUC = 97%), specifically 92% and 86% respectively for MDD and BD. MDD diagnosis was predicted by high levels of markers related to both pro-inflammatory (i.e. IL-1β, IL-6, IL-7, IL-16) and regulatory responses (IL-2, IL-4, and IL-10), whereas BD by high levels of inflammatory markers (CCL3, CCL4, CCL5, CCL11, CCL25, CCL27, CXCL11, IL-9 and TNF-α). Conclusions Our findings provide novel tools for early diagnosis of BD, strengthening the impact of biomarkers research into clinical practice, and new insights for the development of innovative therapeutic strategies for depressive disorders.
Chapter
The rapidly growing field of immunopsychiatry combines expertise and insights from immunology, psychiatry and neuroscience to understand the role of inflammation and other immune processes in causing and treating mental illness. This represents a major shift in mental health science, traditionally focused on psychological and neuronal mechanisms of depression, psychosis and dementia. This book provides the first comprehensive overview of recent, inter-disciplinary research linking disordered function of the immune system to the brain and mental illness. It offers a broad and deep perspective on the implications of immune system involvement in psychiatric disorders, including a balanced focus on basic science and clinical applications. Chapters cover the scientific evidence linking immune processes to major mental illnesses such as schizophrenia, depression, anxiety and dementia. An invaluable guide for graduate students, doctors in training, scientific researchers and others interested in the link between the immune system and mental health.
Article
Full-text available
Introduction: Previous research delivers strong indications that inflammatory activation leads to treatment resistance in a subgroup of patients with Major Depressive Disorder (MDD). Thus, tailored interventions are needed. The present study aimed to find potential biomarkers that may enable patients to be stratified according to immune activation. Methods: A phase IIa randomized placebo-controlled trial was performed to assess levels of inflammatory compounds in responders/remitters and non-responders/non-remitters to sertraline plus celecoxib ( n = 20) and sertraline plus placebo ( n = 23). Levels of macrophage migration inhibitory factor, neopterin, and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay; response and remission were measured by reduction of the Montgomery Åsberg Depression Rating Scale score. Results: Both treatment groups showed a significant decline in depression symptoms, but no difference was found between groups. A clear pattern emerged only for macrophage migration inhibitory factor: placebo remitters showed significantly lower baseline levels than non-remitters (a similar trend was seen in responders and non-responders) while celecoxib responders showed a trend for higher baseline levels than non-responders. Conclusion: Small subsample sizes are a notable limitation, wherefore results are preliminary. However, the present study provides novel insights by suggesting macrophage migration inhibitory factor as a promising biomarker for treatment choice. The trial was registered in EU Clinical Trials Register (EU-CTR): https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-011990-34/DE , EudraCT-No.: 2009-011990-34.
Chapter
The clinical relationship between mental disorders and cardiovascular disease and risk factors is highly important with serious consequences for morbidity and mortality. A key biological mechanism in this complex and bidirectional relationship is related to immune dysregulation and inflammation in particular. This review critically evaluates the existing literature on the bidirectional nature of this relationship, the contributing clinical factors, and the role of inflammation in prevalent risk factors for both mental disorders and cardiovascular disease including obesity, endothelial dysfunction, and diabetes mellitus type 2. This chapter outlines the lines of biological mechanisms in the bidirectional relationship between mental disorders and cardiovascular disease by exemplifying this using depression as a common disorder. This focus on the role of immune dysregulation and inflammation in these risk factors and comorbid disease suggests new avenues for identifying and possibly treating early patients at risk, but also it opens up novel and preventive treatments such as the use of anti-inflammatories for both types of conditions.
Article
Full-text available
Lymphocyte response to stimulation with phytohaemagglutinin (PHA) was assessed in 11 patients with major depression and 8 subjects anticipating bereavement, in order to examine whether altered immune response (PHA stimulation index) was more closely related to depressed mood than to sleep and weight changes. No significant relationship was found between sleep or weight changes and immune response. Depression, measured using the HRSD (with and without sleep scores) and the BDI, was related differently in the two groups. For the depressed patients, increasing depression was associated with reduction in immune response; among those anticipating bereavement (with low depression scores), increasing depression was associated with enhanced immune response. A regression curve using data from both samples demonstrated an inverted 'U'-shaped curve relating immune response to mild and severe depressed states. The results of this study suggest a hypothesis that may explain previous discrepant results and which requires testing on more subjects.
Article
Full-text available
Depression has been associated with both suppression and enhancement of various aspects of immune functioning. It was of interest to determine whether cytokine alterations associated with depression, including interleukin-1 (IL-1beta) and interleukin-2 (IL-2), were related to the neurovegetative symptom profile or to the chronicity of the illness. Circulating ACTH, cortisol, norepinephrine (NE) and epinephrine levels, and production of IL-1beta and IL-2 from mitogen-stimulated lymphocytes were assessed in classical major depression, atypical depression (ie, with reversed neurovegetative features), and dysthymia (chronic depression without comorbid major depression) with either typical or atypical profiles, as well as nondepressed control subjects. Among atypical depressives, plasma ACTH levels were elevated while cortisol was reduced relative to controls. Irrespective of neurovegetative profile, IL-1beta production was increased in dysthymic patients, and was highly correlated with age-of-onset and duration of illness. In contrast, IL-2 production was reduced in each of the groups, although less so among atypical major depressives. Moreover, IL-2 production in the depressive groups was directly related to plasma NE levels. While neither depressed mood per se nor neurovegetative features accounted for this effect, it seemed likely that chronicity of illness or age-of-onset were associated with cytokine alterations. Given that circulating cytokines influence neuroendocrine functioning, and may affect neurovegetative features, a role for interleukins may exist with respect to the pathophysiology of certain subtypes of depression.
Article
• The Composite International Diagnostic Interview (CIDI), written at the request of the World Health Organization/US Alcohol, Drug Abuse, and Mental Health Administration Task Force on Psychiatric Assessment Instruments, combines questions from the Diagnostic Interview Schedule with questions designed to elicit Present State Examination items. It is fully structured to allow administration by lay interviewers and scoring of diagnoses by computer. A special Substance Abuse Module covers tobacco, alcohol, and other drug abuse in considerable detail, allowing the assessment of the quality and severity of dependence and its course. This article describes the design and development of the CIDI and the current field testing of a slightly reduced "core" version. The field test is being conducted in 19 centers around the world to assess the interviews' reliability and its acceptability to clinicians and the general populace in different cultures and to provide data on which to base revisions that may be found necessary. In addition, questions to assess International Classification of Diseases, ninth revision, and the revised DSM-III diagnoses are being written. If all goes well, the CIDI will allow investigators reliably to assess mental disorders according to the most widely accepted nomenclatures in many different populations and cultures.
Article
• Depression and alcohol abuse have been associated with alterations in cell-mediated immune function. This study directly compared the effects of depression, alcoholism, and their joint contribution to reduce natural killer cell cytotoxicity. Natural killer cell activity was significantly lower in both depressed (n =18) and alcoholic (n =19) patients compared with control subjects (n =50). In addition, patients with a dual diagnosis of either alcohol abuse and secondary depression (n = 9) or depression with a history of alcohol abuse (n 26) demonstrated a further decrease in natural killer cell activity compared with that found in patients with either depression or alcoholism alone. While both depression and alcoholism are separately associated with a reduction of natural killer cell activity, subgroups of patients in whom the diagnoses of alcoholism and depression coexist show a further decrement in natural killer cell function.
Article
Im Rahmen von Psychopharmaka-Therapien wurde die Hamilton-Depressions-Skala bei 197 psychiatrischen Patienten je dreimal verwendet; dabei wurde eine erweiterte Version (24 Symptome) der Hamilton-Skala bentzt, die die ursprngliche miteinschliet. Verschiedene formale Analysen (Symptomhufigkeiten, Einflu von Geschlecht, Itemanalysen, Konsistenz schtzung, Faktorenanalysen) lassen folgende Schlufolgerungen zu: Bei der ursprnglichen Fassung ist die einfaktorielle Auswertung am adquatesten; mehrere Faktoren sind nicht anzunehmen. Bei der erweiterten Version (vor allem in USA gebraucht) ist zwar die Einfaktorenlsung ebenso zu empfehlen, doch knnte man auch die Zweifaktorenlsung in Betracht ziehen, bei der zwischen gehemmt-depressiven und somatisch-depressiven Aspekten unterschieden wird. Der Gesamtwert bei der Hamilton-Skala ist von befriedigender Konsistenz (Reliabilitt) und kaum vom Geschlecht abhngig.Within the scope of psychopharmacologic therapies, the Hamilton Rating Scale for Depression was applied 3 times on each of 197 psychiatric patients. An extended version (24 symptoms) of the Hamilton Scale was employed, which included the original symptoms. Various formal analyses (frequency of symptoms, influence of sex, item analyses, estimation of reliability, factor analysis) allow the following conclusions: With the original version, the single factor solution is the most consistent; several factors are not acceptable. With the extended version (used in the U. S. A.) the single factor solution can be equally recommended, but the two factor solution could also be taken into consideration, whereby a distinction is made between retarded depression and somatic depression aspects. The total score of the Hamilton Scale is satisfactorily consistent and hardly dependent on sex.
Article
Natural killer (NK) cell activity was evaluated in 34 ambulatory patients with Major Depressive Disorder (MDD) and 21 healthy controls. No mean differences between the groups were found. However, female depressives (n = 19) exhibited higher NK activity than female controls (n = 14). The relationship between cortisol secretion and NK activity was examined using an integrated cortisol value derived from multiple blood samples taken between 1:00 and 4:00 pm. This comprehensive assessment of cortisol secretion circumvents spurious “single stick” cortisol values and provides a more accurate determination of hypercortisolemia than the dexamethasone suppression test. NK activity in depressives with cortisol hypersecretion (>11 μg/dl) (n = 7) was no differnt than NK activity in depressives and controls with normal cortisol secretion. Furthermore, there was no correlation between cortisol secretion and NK activity in any of the groups. These results indicate that decreased NK activity is not a consistent finding in MDD and cannot be predicted by the presence of hypercortisolemia in these patients.
Article
We examined interleukin-2 (IL-2) related immune pathways in depression to elucidate mechanisms underlying various immunological disturbances associated with depression. Subjects comprised 35 unmedicated patients with a major depressive episode without psychotic features and 36 age- and sex-matched healthy volunteers. The immune parameters examined included the numbers of B and T cells, IL-2 receptor-mediated blastoformation (IL-2R-mediated blastoformation), IL-2 production and expression of the IL-2 receptor alpha-subunit. The patients with a severe episode showed significantly lower IL-2R-mediated blastoformation than the controls. There was a statistically significant negative correlation between IL-2R-mediated blastoformation and the severity of depression at the time of entry. The reduced IL-2R-mediated blastoformation may partly explain several previously reported abnormal immune functions associated with depression.
Article
During 1975 twenty-six bereaved spouses took part in a detailed prospective investigation of the effects of severe stress on the immune system. T and B cell numbers and function, and hormone concentrations were studied approximately 2 weeks after bereavement and 6 weeks thereafter. The response to phytohaemagglutinin was significantly depressed in the bereaved group on the second occasion, as was the response to concanavalin A at 6 weeks. There was no difference in T and B cell numbers, protein concentrations, the presence of autoantibodies and delayed hypersensitivity, and in cortisol, prolactin, growth hormone, and thyroid hormone assays between the bereaved group and the controls. This is the first time severe psychological stress has been shown to produce a measurable abnormality in immune function which is not obviously caused by hormonal changes.
Article
We investigated subsets of peripheral immunologic cells in 12 drug-free patients affected by major depression according to DSM-III-R criteria, and who had recent evidence of somatic diseases. They were compared with 10 drug-free depressives, with 10 patients with panic disorder, and with 12 healthy volunteers, all without somatic disease. The immune subsets were measured by flow cytometry. The results showed that both groups of depressives had the same abnormalities in immune cells compared with the healthy volunteers or the panic disorder patients; in particular they presented a lower number of CD3+, CD8+ and HLA-DR+. The patients with panic attacks did not differ from healthy controls, except for CD4+ cells which were significantly lowered, even in comparison with the depressive groups. These data, although preliminary and in a small sample, suggest that some immune parameters may be influenced by the presence of a major psychiatric disorder.
Article
The effects of major depression on peripheral blood natural killer cell phenotypes and natural killer cell activity were studied by comparing depressed and normal control subjects. Depressed subjects exhibited (1) significant reductions in Leu-11 (CD16) natural killer effector cells and natural killer cell activity and (2) a dissociation of the normal positive correlation between the percentage of Leu-11 cells and natural killer cell activity. These findings suggest that alterations in the availability and the killing capacity of circulating Leu-11 natural killer cells appear to be responsible for depression-related reductions in natural killer cell activity. Moreover, men with major depression showed marked reductions in Leu-11 cells, natural killer cell activity, and Leu-7 (HNK-1) lymphocytes compared with normal control men. By contrast, depressed women did not differ significantly from normal control women on any of these three immune function measures. Severity of depression as assessed by Hamilton Rating Scale for Depression scores was not associated with natural killer cell activity or Leu-7 lymphocyte levels in either men or women with major depression. Hamilton Rating Scale for Depression severity ratings were, however, strongly inversely correlated with Leu-11 lymphocyte counts among men, but not women, with major depression. These data begin to elucidate the immunological mechanisms by which natural killer cell activity is altered in depression and suggest that some measures of immunity may be differentially affected in male and female subjects with the syndrome of major depression.
Article
Recently, some investigators have established a blunted natural killer cell activity (NKCA) in severely depressed patients. In order to replicate these findings NKC cytotoxicity assays--on fresh cell suspensions in human plasma and fetal calf serum--were performed in healthy controls and depressed inpatients. Instead of the commonly used 51Cr-release assay we have used a fluorescent NKC cytotoxicity assay, which allows a greater sensitivity. We observed a significantly blunted NKCA in melancholic patients as compared with healthy controls and minor depressives, whilst simple major depressives exhibited an intermediate position. NKC cytotoxicity assays in fetal calf serum were significantly and negatively correlated with the severity of illness. We were unable to establish any relationship between NKCA and measures of hypothalamic-pituitary-adrenal-axis function, such as baseline, postdexamethasone plasma cortisol and 24 hr urinary cortisol secretion. In addition, we did not find any effects of dexamethasone administration (1 mg orally) on NKCA.
Article
Because recent research reports indicated clinical and biological differences in major depression with and without comorbid Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) panic disorder, and as altered immune measures were reported in selected subgroups of depressive patients, we investigated 51 pairs of major depressive episode (MDE) subjects, and gender- and age-matched healthy controls in order to determine if T lymphocytes number and function abnormalities were associated with Panic Disorder comorbidty. We found that those MDE subjects with DSM-III-R panic disorder (PD) had greater numbers of T cells (p less than 0.05) and PHA mitogen (p less than 0.05) responses than depressive patients without PD, as well as increased phytohemagglutinin (PHA) (p less than 0.05) concanavalin A (ConA) (p less than 0.02) mitogen responses compared to their controls. These data suggest that panic disorder comorbidity significantly contributes to the variance of immunologic parameters in major depression and has to be carefully assessed within psychoimmunological studies of psychiatric patients with affective disorders.
Article
The mitogen-induced lymphocyte proliferative response and its sensitivity to in vitro (10(-10)-10(-6) M) dexamethasone (DEX) administration were investigated in 12 severely depressed patients and 13 healthy controls. Patients with major depressive disorder exhibited no impairment of lectin-induced blastogenesis, but a significantly weaker suppressive effect of in vitro DEX on 1.0 microgram/ml phytohemagglutinin A-induced proliferation. The inhibitory potency of in vitro DEX was inversely correlated with in vivo adrenal cortical hormone levels at 4.00 p.m. These effects were not observed with pokeweed mitogen- and concanavalin A-stimulated cells. There were no correlations with age, weight, sex or severity of depression. These results do not support the hypothesis of a primarily impaired cell-mediated immunity, but might be indicative of reduced glucocorticoid receptor sensitivity in major depressive disorder.
Article
A reduction of natural killer (NK) cell activity has been found in hospitalized patients with major depressive disorder. To examine whether a reduction of NK activity is found in other psychiatric patients or related to the nonspecific effects of hospitalization, NK cell cytotoxicity was compared in hospitalized depressed patients, schizophrenic inpatients, and two groups of controls separately age matched to each patient group. NK activity was significantly (p less than 0.01) lower in depressed inpatients than control subjects. However, in the hospitalized schizophrenic patients values of natural cytotoxicity did not differ from controls. These findings suggest that reduced NK cytotoxicity in depression is independent of the effects of hospitalization.
Article
SYNOPSIS In order to investigate the relationship between the immune apparatus and the hypothalamic–pituitary–adrenal (HPA)-axis activity in depressed patients, we measured in vitro lymphocyte responses to the mitogens Phytohaemagglutinin (PHA), Pokeweed (PWM) and Concanavalin A (Con A) and 8 a.m. baseline cortisol values in plasma, free cortisol excretion in 24 h urine (UFC), basal and post-dexamethasone βendorphin values. Major depressed patients with melancholia/psychotic features exhibited a significantly lower mitogen-induced blast transformation as compared to minor and simple major depressed patients. The lymphocyte responses to the three mitogens were significantly inversely related to baseline cortisol values and postdexamethasone β-endorphin values. The proliferative capacity of lymphocytes to stimulation with PHA and PWM was significantly and positively related to UFC excretion. Up to 45% of the variance in the immune responses to the mitogens was explained by the baseline cortisol, post-dexamethasone β-endorphin and UFC values.
Article
Thirty depressed psychiatric inpatients, including 18 with a diagnosis of major depression, and 25 hospital staff controls were compared with respect to cellular immune function--that is, mitogen responsiveness to concanavalin A (con A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM); natural killer cell (NK) activity; and T cell subsets, including helper/inducer T cells (CD4) and suppressor/cytotoxic cells (CD8). Only physically healthy subjects, who had not used psychoactive medications (except for low dose benzodiazepines) or other medications known to affect the immune system for at least 14 days, were included. Paired comparisons of the immune measures of patients with a DSM-III diagnosis of major depression (n = 18) with their controls demonstrated a statistically significant reduction of the patients' con A response. In addition, the patients with major depression had significantly lower con A and PHA responses than the combined patients with other forms of depression (atypical, dysthymic, or atypical bipolar). There was no indication that severity of depression, dexamethasone suppression test status, benzodiazepine use, or age accounted for the differences in immune function. A possibly important, unexpected finding was that antihistamine use was associated with lower immune function.
Article
The lymphocyte stimulation responses to the mitogens phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed (PWM) were investigated in 30 hospitalized depressed women undergoing a dexamethasone suppression test (DST). Patients were classified according to DSM-III as having major depression with melancholia, without melancholia, and minor depression. The Hamilton Depression Rating Scale (HDRS) and the State-Trait Anxiety Inventory (STAI) were measured. Patients with major depression showed significantly decreased lymphocyte stimulation induced by PHA, Con A, and PWM as compared to those with minor depression. These differences could not be attributed to age, body weight, weight loss, total number of leukocytes, menopausal status, sleep disturbances, concomitant use of low-dosage benzodiazepines or length of drug-free period before testing. The group mean differences in lymphocyte stimulation counts were not affected by the severity of illness or the severity of state and trait anxiety. There were no significant differences in the lymphocyte responses to PHA, Con A, and PWM between DST non-suppressors and DST suppressors. No significant correlations were established between baseline and post dexamethasone cortisol values and the lymphocyte stimulation counts.
Article
Cross-sectional population studies reported decreased mitogen-induced lymphocyte responsiveness in severely depressed patients. This immunologic impairment, indicative of T- and/or B-cell dysfunction, was related to disturbances in the dexamethasone suppression test (DST) and to age effects. Glucocorticoid overdrive, a hallmark for severe depression, exerts immunosuppressive effects through the impact on neutrophils, lymphocytes, and monocytes and natural killer cells (NKC). This paper has analyzed the relation of peripheral blood immune parameters to severe depression, DST results and age. The population consisted of 37 inpatients categorized according to DSM-III as minor depression (300.40, 309.00), simple major depression (296.X2) or major depression with melancholia and/or with psychotic features (296.X3, 296.X4). The number of leukocytes, neutrophils, lymphocytes and monocytes was counted. T-cell (total T-cell, T-helper, T-suppressor, HLA-DR), B-cell (LN1 and immunoglobulin (Ig) receptors), monocytes (M1 and M3 membrane antigens) and NKC activity were identified by phenotype using monoclonal antibodies. No differences were detected between the depressive subgroups for any of the parameters examined. There were no relationships between these immune variables and the severity of illness, DST results or age.
Article
Alterations in peripheral blood leukocyte distribution in major depression, including leukocytosis, neurotrophilia and lymphopenia, have been described. To assess peripheral white blood cells and the hypothalamic-pituitary (HP) axis in drug-free patients with major depression, we measured the total white blood cell count (WBC), and percentage of lymphocytes, and the plasma levels of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH) and prolactin (PRL). Twenty male patients with major depression had relative lymphopenia and leukocytosis when compared with 20 age, sex and racematched control subjects. Elevated Beck and Hamilton depression scores correlated with a decreased percentage of lymphocytes, in a group of all subjects combined. There was a weak tendency for elevated growth hormone to correlate with relative lymphopenia in the control subjects only. Relative lymphopenia and leukocytosis may be a part of the psychobiology of major depression.
Article
To assess cellular immune status and the hypothalamic-pituitary (HP) axis in patients with major depression, we examined peripheral blood mononuclear cells (PBMC) and measured the plasma levels of cortisol, adrenocorticotropin hormone (ACTH), growth hormone (GH), and prolactin (PRL). Twenty patients with major depression were compared with 20 control subjects matched for age, sex, and race. The dose-response curves for concanavalin-A (Con-A) and phytohemagglutinin (PHA) stimulation were not significantly different between the two groups. The patients had decreased Con-A-stimulated T-lymphocyte proliferation when compared to the control subjects, but only at the lowest suboptimal concentration of Con-A. None of the four concentrations of PHA-stimulated proliferation were different between the two groups, neither was PHA-induced interleukin-2 production. Within the patient group only, plasma prolactin (PRL) correlated significantly with stimulated lymphocyte proliferation using two optimal concentrations of PHA and one optimal concentration of Con-A, when the proliferation was expressed using the stimulation index.
Article
Immunologic function as measured by lymphocyte response to phytohemagglutinin (PHA) mitogen was evaluated in 8 psychiatric inpatients. All were less than 45 years of age and had a DSM-III diagnosis of major depression. When patient's immunologic responses were compared with healthy age- and sex-matched controls, a significant increase in PHA mitogen stimulation was observed in the depressed group. Further, a significantly greater variance in PHA response was observed in the patients compared with controls. The literature on depression and immunity is reviewed and the clinical implications of our findings are discussed.
Article
Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/27710/1/0000096.pdf
Article
Natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) were tested in patients with schizophrenia or depression. It was found that NK activity as well as ADCC were significantly lower in both groups, as compared to healthy control individuals (P less than 0.001). Psychopharmacologic treatment with neuroleptics and antidepressives resulted in a significant increase in NK activity and ADCC (P less than 0.005) in patients with schizophrenia but not in treated patients with depression. In patients with schizophrenia, no correlation could be established between the dose of neuroleptic given and the increase in NK activity. Lithium also did not produce an increase in NK activity and ADCC. The addition of serum, derived from untreated patients with schizophrenia, to cell cultures in concentrations of 10 and 20% had an inhibitory effect upon the ADCC and, to a lesser degree, upon NK activity (20% serum concentration only); sera from treatment schizophrenics produced no inhibition of NK activity, but did affect ADCC. No serum-derived inhibitory effect upon either NK activity or ADCC was found to be present in sera from patients with depression. We conclude that lytic effector mechanisms are impaired in patients with schizophrenia or depression and that this defect is reversed in schizophrenic patients on treatment, but not in depressives on therapy. Patients with schizophrenia also tend to have a reversible serum-mediated inhibition of NK activity which is absent in patients with depression.
Article
To assess cellular immune status and the hypothalamic-pituitary axis in patients with major depression, we examined peripheral blood mononuclear cells and measured the plasma levels of four neurohormones. Eleven patients with major depression had increased % of T4 lymphocytes and decreased concanavalin (Con A) stimulated T lymphocyte proliferation when compared with 11 age-, sex-, and race-matched control subjects. Percent of total lymphocytes labeled as all T lymphocytes, all B lymphocytes, and natural killer cells did not differ in the two groups, nor did mitogen-induced interleukin-2 production. These findings support theories of interaction between depression and immune cell function.
Article
The production of interleukin 1 (IL1) and interleukin 2 (IL2) by mononuclear cells (MNC) from untreated rheumatoid arthritis (RA) patients or healthy subjects were examined. After PHA stimulation, patient MNC or T cells produced varying amounts of IL2 that were related to the disease activity: patients suffering from active disease showed a scant production of IL2 while those who had a quiescent disease were high producers. The prior irradiation of unfractionated MNC induced a marked increase of the PHA-stimulated IL2 production in both active and quiescent patients compared to the moderate augmentation observed for controls. On the other hand, irradiation of enriched T cells had an enhancing effect only in the active RA patient group. Concurrently, we found that non T cells from active or quiescent RA patients were fully competent to produce IL1 upon LPS activation. Taken together, these findings suggest that the suppressive activity evidenced by irradiation could be mediated by non T cells in quiescent disease or in absence of illness. On the other hand, both radiosensitive suppressor T and non T cells may interfere in IL2 production by active RA patient lymphocytes.
Article
To explore changes in immune cell status with changes in the hypothalamic-pituitary (HP) axis in 20 patients with major depression as compared with 20 age-, sex-, and race-matched control subjects, we examined peripheral blood mononuclear cells (PBMC) for total T-cells (T3), total B-cells (B1), two T-cell subsets (T4 and T8), and natural killer cells (NKH1), and we measured the plasma level of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), and prolactin (PRL). The ratio of T4/T8 was increased in the patients. Within the group of control subjects only, increasing age correlated significantly with decreasing plasma PRL. Within the group of patients only, GH positively correlated significantly with T8 and NKH1, as did PRL with NKH1. No between-groups difference was found for T3, B1, T4, T8, NKH1, cortisol, ACTH, GH, or PRL.
Article
1. To assess the effect of age on cellular immune status and the HP axis in patients with major depression, we examined peripheral blood mononuclear cells (PBMC) and measured the plasma level of four neurohormones. 2. In 36 subjects, decreasing T lymphocyte response to con A covaried with age. Percent of lymphocytes labeled as T8 lymphocytes tended to decrease and T4/T8 ratio tended to increase with increasing age. 3. Hamilton and Beck scores were significantly different between the two sex and race matched groups of 18 depressed patients and 18 control subjects, and plasma prolactin was significantly higher in depressed subjects. 4. Increasing age correlated with decreasing T lymphocyte response to con A in the combined group of all subjects, and in the control group, but not in the patient group. 5. Hamilton and Beck scores correlated inversely with T lymphocytes response in the combined group of all subjects. 6. Differences in mitogen responsiveness between patient and control groups were not found, having been obscured by the effect of age. 7. These findings indicate the need to age match subjects when studying the interaction between depression and immune cell function.
Article
An impairment in lymphocyte response to mitogen stimulation, a correlate of cell-mediated immunity, has been reported in patients with depressive illness. To investigate whether such impairment in lymphocyte function is related to excessive secretion of cortisol, an immunosuppressive hormone, we compared mitogen-induced lymphocyte proliferation in three groups of subjects: depressed patients with elevated 24-hour urinary free cortisol (UFC) excretion; depressed patients with normal UFC excretion; and normal controls. Depressed patients in both groups showed significant reductions in lymphocyte mitogenic activity, in comparison with the normal controls, but the two depressive groups did not significantly differ from each other in their lymphocytic responses to any of the mitogens used. Furthermore, no significant correlations were found, within depressed patients, between UFC excretion and lymphocyte mitogenic responses. Depression is therefore associated with an impairment in lymphocyte function that cannot be explained solely on the basis of increased cortisol secretion.
Article
The spontaneous and induced interferon (IFN) production in whole blood cultures was examined in 45 psychiatric inpatients and in 65 normal controls. Among inpatients there were 32 who were chronic schizophrenics (14 women, 18 men) and 13 who were severely depressed (11 women, 2 men). The analysis of the pooled results of assays in the heterogeneous population showed that leukocytes of the psychiatric patients produced significantly lower levels of IFN after stimulation with virus (NDV), lipopolysaccharide (LPS), and IFN spontaneously released without the inducers that control cells. In contrast, there was no difference between the psychiatric patients and controls in IFN response to phytohemagglutinin and phorbol myristate acetate (PHA + PMA). The results apparently confirmed observations made by Moises et al (1985) and Katila et al (1989). We have also tested our hypothesis that the statistics may mask the individual pattern of IFN response related to the specific psychiatric diagnosis, however. In fact, in the group of chronic schizophrenics we have found either high or low responders to all IFN inducers (NDV, PHA + PMA and LPS). Furthermore, the patients with high IFN response had dominant positive symptoms of schizophrenia (delusions, hallucinations, bizarre behavior and thought disorder). Whereas, in the patients with low IFN response the negative symptoms prevailed (asociality or withdrawal, flat affect, attention impairment, abolition or apathy). In plasma samples of schizophrenics, factors were detected that transferred a hypersensitivity to the IFN inducers to normal donor leukocytes. For instance, in leukocytes cultured in the presence of plasma from schizophrenics, there were 71% of high IFN responders after stimulation with NDV, versus 26% of high IFN responders in the presence of plasma from normal controls. We suggest that the factors may belong to the class of opioid peptides, which interact with the production of cytokines including IFNs.
Article
One of the most consistently reported immunological abnormalities in major depression is blunted ex vivo natural killer cell activity (NKCA). This study was designed to investigate the number and percentage of circulating natural killer cells (NKC) in a group of patients with unipolar depression. In addition, the number and percentage of other phagocytic/cytotoxic cells were determined. The following cell subsets were investigated: number of leukocytes, monocytes, neutrophils, lymphocytes, NKC (CD16+ or CD56+), and non-MHC-restricted cytotoxic T lymphocytes (CTL) in 17 healthy controls and 79 depressed subjects. There were no differences either in absolute number or percentage of NKC, or CTL between healthy controls, minor, simple major, and melancholic depressed subjects. Depression per se was characterized by a leukocytosis due to monocytosis and neutrophilia. Our results do not support the thesis that depression-related blunted NKCA is caused by a decreased number or percentage of NKC in peripheral blood.
Article
We measured some immunological parameters in 20 hospitalized patients with major depression and 20 age- and sex-matched healthy controls. Both enumeration of immune cells, including T-lymphocyte subpopulations, and assay of T-cell function were studied. White blood cells were evaluated with an automated cell counter, T-cell subsets with an immunobead technique, and T-cell function with a phytohemagglutinin-induced proliferation in vitro assay. We found that T-lymphocyte responses to the mitogen were significantly lower in depressed patients than in controls. All the other parameters were normal. These findings suggest that functional but not numerical changes in T-lymphocytes characterize major depressive disorders.
Article
Previous attempts to establish a relationship between impaired cell-mediated immunity (CMI) and major mood disorders have been limited by a failure to explore the relevance of depressive subcategories or to assess CMI by in vivo methods. In this case-control study CMI was assessed in 57 patients with major depression (31 with melancholic, 26 with non-melancholic disorders), and in age- and sex-matched controls by both in vitro and in vivo immunological techniques. Compared with control subjects and patients with non-melancholic depression, patients with melancholia demonstrated reduced in vivo CMI as