COLLEGIUM INTERNATIONALE NEURO-PSYCHOPHARMACOLOGICUM

Central/Eastern European
C.I.N.P.

(Collegium Internationale Neuro-Psychopharmacologicum)

Regional Committee

Faculty of Medicine MU

Joint CINP-CNPS (Czech Neuropsychopharmacological Society) Symposium: “Inflammatory processes and depression“
held in Brno on the occasion of “Czech-Slovak Psychiatric Conference”, October 12 - 15, 2011

Programme:
H. J. Möller: (Germany): Endocrinological markers in depression
A. Halaris (USA): Pro-inflammatory pathways and depression
D. Jezova (Slovakia): Stress and depression
M. Anders (Czech Republic): Depression and cardiovascular system

ABSTRACTS

DOES THE IMMUNOLOGICAL HYPOTHESES OF DEPRESSION OPEN NEW THERAPEUTIC POSSIBILITIES?
Prof. Dr. Hans-Jürgen Möller, Chairman, Department of Psychiatry
Ludwig-Maximilians-University München
Nussbaumstrasse 7, 80336 Munich, Germany
Tel: +49 89 5160 5501, E-mail: hans-juergen.moeller@med.uni-muenchen.de

Antidepressants, predominantly serotonin and/or norepinephrine reuptake inhibitors, have several limitations in clinical practice: delayed onset of action, partial or non-response, etc. These unmet needs are the background for research in different directions: compounds representing other pharmacological mechanisms, comedication/augmentation strategies, etc. In this context anti-inflammatory agents seem to be of interest.
It has been postulated that an inflammatory mechanism may be involved in the pathogenesis of depression. Furthermore, the activation of the enzyme indoleamine 2,3-dioxygenase (IDO), resulting in a possible increase in quinolinic acid in depression, may also play a key role.
In addition, immunological imbalance results in the increased production of PGE2 in schizophrenia and depression. Although there is evidence supporting the hypothesis that interactions between immune system components, IDO, the serotonergic system and glutamatergic neurotransmission play a key role in schizophrenia and depression, several gaps in knowledge remain, such as regarding the role of genetics, disease course, gender and different psychopathological states. There is evidence indicating that anti-inflammatory therapy may have beneficial effects in depression. COX-2 inhibitors have been tested in animal models and in preliminary clinical trials, demonstrating favourable activity compared with placebo. However, the effects of COX-2 inhibition in the CNS, as well as toward different components of the inflammatory system, kynurenine metabolism and glutamatergic neurotransmission, require further evaluation, which should include clinical trials with larger numbers of patients.

BIOMARKERS OF PRO-INFLAMMATORY PATHWAYS IN DEPRESSION
Angelos Halaris, Department of Psychiatry, Loyola University Stritch School of Medicine, Chicago, Illlinois, USA

Introduction:
Cardiovascular disease (CVD) and depressive illness are two of the world’s leading health problems. Depression is an independent risk factor for cardiovascular mortality following myocardial infarction and its presence is associated with increased CVD events.  The precise mechanisms underlying this co-morbidity elude us. Studies have focused on platelet reactivity, endothelial dysfunction and inflammatory processes. Pro-inflammatory cytokines have been implicated in the etiology of depression (Dantzer et al. 2003 & 2008, Miller et al. 2002 & 2009, Howren et al. 2009).  A causal relationship between pro-inflammatory cytokines  and depression exists in individuals with disorders involving chronic inflammation (Dantzer et al. 2008, Miller et al. 2009). Lab animals exposed to elevated levels of endogenous, or exogenously-administered pro-inflammatory cytokines display a host of depressed-like symptoms, collectively referred to as cytokine-induced “sickness behavior” (Dantzer et al. 2008, Watkins & Maier 2005).  Human studies have shown increased blood concentrations of pro-inflammatory cytokines in depressed adults, and a positive correlation between depressive symptoms and circulating cytokines (Miller et al. 2002,O’Brien et al. 2007). Clinical depression following Interferon therapy is also well known (Miller 2004, Musselman et al. 2001).  Finally, antidepressant effects have been observed following treatment with cytokine inhibitors (Tyring et al. 2006), and in some studies antidepressant treatments have been effective at lowering circulating levels of certain pro-inflammatory cytokines following remission from major depression (Basterzi et al. 2005,Kenis & Maes 2002,O’Brien et al. 2007).
Aims:
Depressive illness shows high co-morbidity with cardiovascular disease (CVD) and may contribute to its development. It is unclear if antidepressant treatment can prevent this outcome. This study was undertaken to better understand the pathophysiology of the co-morbidity between CVD and depression.  We sought to obtain a plasma cytokine and growth factor profile in patients with major depressive disorder (MDD) who lacked any signs of early-stage CVD. MDD patients were compared to age/sex-matched healthy controls and it was determined whether the depressed patients showed normalization of the biomarkers following successful treatment either with the most selective serotonin reuptake inhibitor (SSRI), escitalopram (ESC), or the atypical antipsychotic, quetiapine (QTP), as monotherapeutic agents.
Methods:
MDD patients (N=33) and age-matched HCs (N=25) were enrolled (Table 1). Severity of depression was assessed using the 17-item Hamilton Depression Rating Scale (HAM-D17). Exclusion criteria included cardiovascular or thyroid disease, hypertension, diabetes, smoking, and the presence of other Axis I diagnosis. Controls were screened to be free of physical and mental disease. Patients received escitalopram (ESC) or quetiapine (QTP). ESC dosing began at 10 mg/day and was maintained at 10-30 mg/day. QTP dosing was started at 25 mg/day and was gradually increased up to 300 mg/day. Follow-up assessments occurred at weeks 2, 4, 8, and 12. Post-treatment HAM-D17 scores were used to determine treatment response. A ≥50% reduction in the baseline score constituted remission. Plasma concentrations of interleukin (IL)-1α, IL-1β, IL-2, 4, 6, 8, & IL-10, vascular endothelial growth factor (VEGF), interferon-γ (IFN- γ), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), and epidermal growth factor (EGF) were analyzed using a high-sensitivity biochip immunoassay system Evidence®, Randox Laboratories Ltd. Correlations were sought between the pre- and post-treatment biomarkers and various clinical and psychological rating scales.
Results:

  • The MDD cohort expressed higher levels of inflammatory biomarkers compared to the HC group, with seven of the twelve biomarkers reaching statistical significance (Table 2).  Ratios of these values expressed as MDD:HC (with HC=1) will be presented.
  • After twelve weeks of antidepressant treatment, there was a significant decrease in mean HAM-D17 score.
  • Of the 33 patients, 21 (64%) experienced remission, 5 (15%) patients were partial responders, and 7 (21%) did not respond (Figure 4).  Despite these impressive response rates, we did not observe any significant alterations in cytokine or growth factor levels after twelve weeks of treatment.
  • An interesting spiking trend was observed, however, for IL-8, VEGF, and EGF at week 8 of treatment.

Conclusion:
Our study provides compelling evidence that depression and immune dysregulation are intimately linked.  Compared to HC subjects, MDD patients express significantly higher levels of circulating pro-inflammatory cytokines/chemokines and growth factors including: IL-2,4,6,8, VEGF, TNF-α, and MCP-1. Mean plasma concentrations of these biomarkers were 1.5 to 2.9 times higher in the MDD than the HC group at baseline.  Although, we obtained significant treatment responses accompanied by a large remission rate, we did not find a significant change in the cytokine and growth factor profile after twelve weeks of treatment. This finding may indicate that normalization of these biomarkers may necessitate a longer treatment period.  It may also be inferred that low-grade systemic inflammation is a trait marker of MDD, and that antidepressant treatment over a twelve week period is not sufficient to normalize inflammatory biomarker levels despite a significant resolution of depressed symptomatolgy. Interestingly, despite significant elevations in nearly all pro-inflammatory cytokines profiled in the MDD cohort, levels of IL-10, (an anti-inflammatory cytokine) were nearly identical in the MDD and HC groups. Collectively, these results indicate that depression is accompanied by a shift favoring pro-inflammatory cytokines.. The spiking trend observed for IL-8, VEGF, and EGF at week 8 of treatment warrants further investigation, and may provide mechanistic insight into the underlying endothelial changes associated with a disease progression and possibly with antidepressant treatment. This is the first study to report a cytokine and growth factor profile in MDD patients, and the effects of antidepressant monotherapy over a twelve week treatment period.
References:
Basterzi et al., 2005 A.D. Basterzi, C. Aydemir, C. Kisa, S. Aksaray, V. Tuzer, K. Yazici and E. Goka, IL-6 levels decrease with SSRI treatment in patients with major depression, Human Psychopharmacology 20 (2005), pp. 473–476.
Capuron and Miller, 2004 L. Cytokines and psychopathology: lessons from interferon-alpha, Biological Psychiatry 56 (2004), pp. 819–824.
Capuron and Dantzer, 2003 L. Capuron and R. Dantzer, Cytokines and depression: the need for a new paradigm, Brain, Behavior, and Immunity 17 (Suppl. 1) (2003), pp. S119–S124.
Dantzer et al., 2008a R. Dantzer, L. Capuron, M.R. Irwin, A.H. Miller, H. Ollat, V.H. Perry, S. Rousey and R. Yirmiya, Identification and treatment of symptoms associated with inflammation in medically ill patients, Psychoneuroendocrinology 33 (2008), pp. 18–29.
Dantzer et al., 2008b R. Dantzer, J.C. O’Connor, G.G. Freund, R.W. Johnson and K.W. Kelley, From inflammation to sickness and depression: when the immune system subjugates the brain, Nature Reviews Neuroscience 9 (2008), pp. 46–56.
Howren et al., 2009 M.B. Howren, D.M. Lamkin and J. Suls, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Medicine 71 (2009), pp. 171–186.
Kenis and Maes, 2002 G. Kenis and M. Maes, Effects of antidepressants on the production of cytokines, International Journal of Neuropsychopharmacology 5 (2002), pp. 401–412.
Miller et al., 2002 G.E. Miller, C.A. Stetler, R.M. Carney, K.E. Freedland and W.A. Banks, Clinical depression and inflammatory risk markers for coronary heart disease, American Journal of Cardiology 90 (2002), pp. 1279–1283.
Miller et al., 2009 Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological Psychiatry 2009.
Musselman et al., 2001 D.L. Musselman, D.H. Lawson, J.F. Gumnick, A.K. Manatunga, S. Penna, R.S. Goodkin, K. Greiner, C.B. Nemeroff and A.H. Miller, Paroxetine for the prevention of depression induced by high-dose interferon alpha, New England Journal of Medicine 344 (2001), pp. 961–966.
O’Brien et al., 2007 S.M. O’Brien, P. Scully, P. Fitzgerald, L.V. Scott and T.G. Dinan, Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy, Journal of Psychiatric Research 41 (2007), pp. 326–331.
Tyring et al., 2006 S. Tyring, A. Gottlieb, K. Papp, K. Gordon, C. Leonardi, A. Wang, D. Lalla, M. Woolley, A. Jahreis, R. Zitnik, D. Cella and R. Krishnan, Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial, Lancet 367 (2006), pp. 29–35.
Watkins and Maier, 2005 L.R. Watkins and S.F. Maier, Immune regulation of central nervous system functions: from sickness responses to pathological pain, Journal of Internal Medicine 257 (2005), pp. 139–155.

NEUROPEPTIDES AND STEROIDS IN STRESS AND DEPRESSION
D. Ježová, Laboratory of Pharmacological Neuroendocrinology, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia

Immune functions of the body are significantly affected by stress exposure and stress is considered to be one of the main risk factors in the development and course of depressive disorders. During stress, the coordination of immune, physiological and behavioral responses is played mainly by the neuropeptide corticotropin-releasing factor. We and others have shown that the expression of this neuropeptide is increased in animal models of depression (Duncko et al. 2001). There are several other neuropeptides and hormones released during stress, some of them having a low and others a high impact on the immune system.
The best known hormones being involved in both the stress response and the control of immune functions are glucocorticoids. There is substantial evidence showing a link between changes in cortisol release or action and the pathogenesis of depression or anxiety disorders. It is generally accepted that glucocorticoids can be harmful to the brain; however, the evidence has been obtained in animal models with pharmacological doses of glucocorticoids and has been based on much higher stress-induced increases in corticosterone in rodents compared to increases in cortisol in humans. In opposite, we have shown in humans that enhanced release of cortisol during stress may be associated with better cognitive performance. In male subjects with hegh trait anxiety we showed that lower adrenocorticotropin (ACTH) and cortisol responses during stress were associated with exaggerated perception of stress and worse mental performance (Duncko et al. 2006). In women, stress-induced cortisol concentrations positively correlated with cognitive performance in subjects with low trait anxiety (Hlavacova et al. 2008). Thus, both exaggerated and inadequate release of glucocorticoids may be a negative feature of the stress response.
Oxytocin is a stress hormone with a limited influence on the immune functions and the physiological purpose of stress-induced oxytocin release is not understood. We have introduced a model simulating stress-induced rise in circulating oxytocin by its chronic administration via osmotic minipumps and have suggested that the role of oxytocin released during stress may be in modulating the hypothalamic-pituitary-adrenocortical axis and selected sympathetic functions. Moreover, we have obtained evidence for cardioprotective actions of oxytocin as well as for a positive influence of long-term increase in circulating oxytocin on the adipose tissue differentiation (Ondrejcakova et al. 2010; Eckertova et al. 2011).
In opposite to glucocorticoids, the mineralocorticoid hormone aldosterone may induce pro-inflammatory effects. Aldosterone is released during stress, however until recently, it has not been considered to modulate the mood. We have shown its anxiogenic and depressogenic actions (Hlavacova et al. 2011). Treatment of rats with aldosterone via osmotic minipumps (14 days) induced an anhedonic state, depression-like behavior as well as increased anxiety. Hippocampal gene expression profiling revealed a number of genes significantly altered by aldosterone treatment. The main transcriptional change was identified in genes related to inflammation, glutamatergic activity and synaptic and neuritic remodeling. Moreover, an overlap between aldosterone- and stress-regulated genes was observed. Thus, aldosterone treatment induced changes relevant to the etiology of major depressive disorder. It may serve as a new animal model of depression, which includes also enhanced expression of genes related to inflammatory pathways (Hlavacova et al. 2011).
Supported by grants of APVV-0028-10 and Vega 2/0118/1.

References

  • Duncko R., Kiss A., Skultetyova I., Rusnak M., Jezova D.: Corticotropin-releasing hormone mRNA levels in response to chronic mild stress rise in male but not in female rats while tyrosine hydroxylase mRNA levels decrease in both sexes. Psychoneuroendocrinology 26: 77-89, 2001
  • Duncko R, Makatsori A, Fickova E, Selko D, Jezova D. Altered coordination of the neuroendocrine response during psychosocial stress in subjects with high trait anxiety. Prog Neuropsychopharmacol Biol Psychiatry 30(6):1058-66, 2006
  • Hlavacova N, Wawruch M, Tisonova J, Jezova D. Neuroendocrine activation during combined mental and physical stress in women depends on trait anxiety and the phase of the menstrual cycle. Ann N Y Acad Sci 1148: 520-525, 2008
  • Ondrejcakova M, Bakos J, Garafova A, Kovacs L, Kvetnansky R, Jezova D. Neuroendocrine and cardiovascular parameters during simulation of stress-induced rise in circulating oxytocin in the rat. Stress 13(4):314-22, 2010
  • Eckertova M, Ondrejcakova M, Krskova K, Zorad S, Jezova D. Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis. Br J Pharmacol.: 162(2): 452-463, 2011
  • Hlavacova N, Wes PD, Ondrejcakova M, Flynn ME, Poundstone PK, Babic S, Murck H, Jezova D: Subchronic treatment with aldosterone induces depression-like behaviors and gene expression changes relevant to major depressive disorder. Int J Neuropsychopharmacol, 2011 (in press)

VZTAH DEPRESIVNÍ PORUCHY A KARDIOVASKULÁRNÍHO SYSTÉMU DEPRESSION AND CARDIOVASCULAR SYSTEM
M Anders
Psychiatrická klinika 1. LF UK a VFN Praha, Praha, Česká Republika

Summary:
Depressive disorders and cardiovascular disease are closely interconnected by a whole range of pathophysiological mechanisms. Essential are three mechanisms: activation of the hypothalamus-hypohysis-adrenal axis with a subsequent increase in sympathetic-adrenal system activity, decrease in vagal tone with a decrease in heart rate variability, and alterations of thrombogenesis with increased platelet aggregability. Behavioural mechanisms and psychosocial factors are also integral to this common pathophysiology. Recent research has focused mainly on studying various forms of stress, as well as changes and possibilities of influencing the autonomous vegetative system. Temporal aspects of the incidence and development of depressive episodes in relation to cardiovascular disease and subsequent cardiovascular morbidity and mortality are being studied, as well as general mortality risk factors.  These findings are important for clinical practice. It is evident that in patients with untreated depressive disorder, the risk of developing cardiovascular disease is significantly higher than in patients suffering from a depressive disorder being treated with anti-depressants. From the data published so far, it may be surmised that depressive disorders in patients with cardiovascular disease may be reliably and safely treated with anti-depressants that act as inhibitors of serotonin re-uptake.
Key words: cardiovascular system, cyrdiovascular disease, depressive disorder, stress factors, psychosocial factors.
Bylo opakovaně prokázáno, že depresivní porucha může být jak příčinou, tak i následkem tělesného onemocnění. Depresivní porucha významně zvyšuje riziko mortality z důvodů kardiovaskulární choroby, a to významněji u kardiologicky nemocných než u zdravých jedinců, přičemž riziko závisí na stupni závažnosti srdeční choroby. Dvakrát vyšší úmrtí existuje u osob trpících tzv. malou depresí (dle klasifikace DSM-IV = méně vyjádřené depresivní příznaky) a více než třikrát vyšší u osob s tzv. velkou depresí (dle klasifikace DSM-IV = jasně vyjádřené symptomy depresivní epizody). Afektivní porucha se může vyskytnout u jedince poprvé v životě v přímé souvislosti např. s infarktem myokardu, potom hovoříme o organické depresivní poruše (dle MKN-10 F 06.32). Vliv a okolnosti kardiovaskulárního onemocnění také mohou vyvolat depresivní potíže u jedince, který již v minulosti depresi prodělal nebo se pro ni léčí. Potom označíme poruchu spíše jako exacerbaci periodické depresivní poruchy (F 33.x), přičemž somatické onemocnění představuje provokující faktor již přítomné psychické choroby.
Zvýšené riziko mortality kardiovaskulárních chorob bylo nalezeno i u depresivních osob bez srdečního onemocnění. Depresivní porucha tedy není jen markerem závažnosti srdeční choroby, ale sama přispívá k jejímu rozvoji a představuje tak vedle tzv. „tradičních“ rizikových faktorů – arteriální hypertenze, hypercholesterolémie, kouření cigaret, diabetes mellitus – samostatný rizikový faktor pro její rozvoj. Kardiovaskulární choroby a depresivní poruchy tak představují dva na sobě nezávislé a svým působením aditivní činitele zvyšující mortalitu na kardiovaskulární choroby. Z tohoto pohledu je detekce depresivní poruchy a její včasná a správně vedená léčba u kardiálně nemocných nesmírně důležitá.
Přesný mechanismus jakým ovlivňuje přítomnost depresivní poruchy vznik a rozvoj kardiovaskulárních chorob a naopak je dosud nejasný. Je však prokázáno, že se nejedná pouze o jeden jediný mechanismus, ale o vzájemnou souhru více faktorů. Na základě existujících literárních přehledů se dá usuzovat, že jako nejpravděpodobnější se jeví kombinace mechanismů biologických a behaviorálních. Psychosociální faktory a nežádoucí, psychické, účinky některých kardiologických preparátů např. alfa blokátory, metyldopa, klonidin aj. hrají neméně významnou roli ve společné patofyziologii těchto dvou diagnostických jednotek. Mezi nejdůležitější biologické faktory patří aktivace osy hypothalamo–pituito–adrenální osy, dysbalance autonomního vegetativního systému a z toho plynoucí změny variability srdečního rytmu a snížená senzitivita baroreflexu, změny v imunitním systému včetně ovlivnění zánětlivých procesů a ve složení nenasycených mastných kyselin a zvýšená trombogeneze. Depresivní porucha je spojována se změnami životního stylu nemocných. Depresivní pacienti jsou nuceni měnit celou řadu návyků a to jak škodlivých, tak i prospěšných. Prožívají změnu ve svém chování, obtížněji zvládají denní úkoly, povinnosti a stereotypy, mění návyky v péči o sebe i okolí. Nezvládají práci, nemyslitelné jsou pro ně běžné fyzické aktivity, včetně pravidelných vycházek či sportování. Mění dietní zvyky, u kuřáků stoupá počet vykouřených cigaret. Cítí ohrožení na životě i ohrožení existenční, protože jsou vytrženi z plnění pracovních a sociálních rolí. Podíváme-li se na tyto symptomy z druhé strany, bývají nuceně navozeny též při onemocnění závažnou kardiovaskulární chorobou.
Závěrem lze konstatovat, že depresivní porucha představuje samostatný rizikový faktor při vzniku a rozvoji kardiovaskulárních chorob, jak u zdravých jedinců, tak u nemocných trpících kardiovaskulárními chorobami. Při vzniku těchto chorob hraje stejně významnou roli jako např. porucha lipidového spektra, hypertenze, vyšší věk, ženské pohlaví nebo kuřáctví. Depresivní porucha a kardiovaskulární choroby mají prokazatelné společné patofyziologické koreláty.
Tato práce byla podpořena výzkumným záměrem MSM 0021620849.


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