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Diego Centonze UOSD Centro Sclerosi Mul2pla, Policlinico Tor Vergata & Laboratorio di Neuroimmunologia e Plas2cità Sinap2ca, IRCCS Fondazione Santa Lucia, Roma
INFIAMMAZIONE E DISTURBI DELL’UMORE
1: Leonard BE. The concept of depression as a dysfunction of the immune system. Curr Immunol Rev. 2010 Aug;6(3):205-212. 2: Catena-Dell'Osso M, Bellantuono C, Consoli G, Baroni S, Rotella F, Marazziti D. Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development? Curr Med Chem. 2011;18(2):245-55. 3: Janelidze S, Mattei D, Westrin Å, Träskman-Bendz L, Brundin L. Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav Immun. 2011 Feb;25(2):335-9.- 4: Zhu CB, Lindler KM, Owens AW, Daws LC, Blakely RD, Hewlett WA. Interleukin-1 receptor activation by systemic Lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology. 2010 Dec;35(13):2510-20.
5: Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010 Oct 15;68(8):748-54. 6: Warriner EM, Rourke SB, Rourke BP, Rubenstein S, Millikin C, Buchanan L, Connelly P, Hyrcza M, Ostrowski M, Der S, Gough K. Immune activation and neuropsychiatric symptoms in HIV infection. J Neuropsychiatry Clin Neurosci. 2010 Summer;22(3):321-8. 7: Maes M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Jun 20. [Epub ahead of print] 8: Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K. Altered expression of genes involved in inflammation and apoptosis in Frontal cortex in major depression. Mol Psychiatry. 2010 May 18. [Epub ahead of print]
“… ques(onnaires from 2391 pa(ents, including 1528 men (63.9%) and 863 women (36.1%). Depressive symptoms were observed in 1482 pa(ents (62% overall; females, 63%; males, 61%) ...”
“…Emo(onal suffering due to psoriasis can lead to depression and suicidal idea(on; indeed, recent studies have shown that psoriasis is associated with a high risk of suicide…”
Recent studies have suggested that inflammatory responses may play an important role in the pathophysiology of depression. In fact, depressed individuals have been found to have higher levels of pro-‐inflammatory cytokines, especially tumor necrosis factor-‐alpha (TNF-‐a) and IL-‐6. This appears to be independent of any pre-‐exis2ng chronic inflammatory disorders. In this ar2cle, various studies correla2ng increased levels of cytokines to depression are reviewed. As much as 60% of individuals with psoriasis also suffer from clinical depression. TNF-‐a antagonists, frequently used in the treatment of psoriasis, may be helpful in directly reducing depressive symptoms for paPents with psoriasis and other chronic inflammatory condiPons
Ü Ansia clinicamente significativa nel 25% dei pazienti Ü Associata con sintomi fisici, disfunzioni sociali e pensieri suicidari Ü Frequentemente sottostimata
Disturbi dell’umore in corso di Sclerosi Multipla
01020304050607080
depressione
agitaz
irritabità
ansia
disinibizione
apatia
euforia
allucinazione
deliri
79 40 35 37 13 20 13 10 7
depressione
agitaz irritabità ansia disinibizione
apatia euforia allucinazione
deliri
Diaz-Olavarrieta. J Neuropsychiatry Clin Neurosci 11: 51-7, 2009
% Depressione in SM
10 20 30 40 50 60
Schiffer 1983
Minden 1987
Joffe 1987
Feinstein
Sadovnick 1996
Berg 2000
Zorzon 2001
Chwastiak 2002
Patten 2003
36 54 42 40 50 40 18 42 25,7
Schiffer 1983
Minden 1987
Joffe 1987
Feinstein
Sadovnick 1996
Berg 2000
Zorzon 2001
Chwastiak 2002
Patten 2003
Canada § 145 decessi su 3126 casi di SM
§ 56 per complicazioni SM § 63 per altre cause
§ di cui 8 suicidi (23.6%) § (5.5% di tutti i decessi)
§ Aumento del tasso di suicidi del 7.5% rispetto alla popolazione generale
§ Sadovnick et al. Neurology 41: 1193-6, 2001
Danimarca § 53 suicidi su 5525 SM (0.96%) § Maggior rischio per:
§ M con esordio < 30 aa. § F con esordio > 30 aa. § durante il primo anno di
diagnosi § Stenager. JNNP 55: 542-5, 2004
SM: aumento rischio di suicidio
Vivere soli, depressione grave e alcoolismo: “85% predictive accuracy for suicidal intent”
Feinstein. Neurology 59: 674-8, 2002
RisultaP studi sulla frequenza di suicidio nella SM
► Intenzioni di suicidio: 29% ► Tenta2vi di suicidio: 6.4% ► Popolazione generale: Ø Intenzioni di suicidio : 13.5% Ø Tenta2vi di suicidio : 3.8%
Feinstein et al, 2002
§ Valutato “effect size” tra 20 studi di confronto tra SM e controlli sani e 21 tra SM e altre patologie croniche
§ Pazienti con SM § con disabilità medio-leggera più depressi rispetto ai
controlli § più depressi rispetto ai pazienti neuromuscolari
Depressione in SM: confronto con altre patologie neurologiche
Dalton. Neuropsychology 19: 152-8, 2005.
§ A current exacerbation in symptoms, greater uncertainty of illness,
§ were related to depression.
§ The prevalence of emotional disturbance was
§ 90% in exacerbating or progressing patients,
§ 39% in stable patients, § The presence … was not related
§ to age, sex, or other demographic variables,
§ to duration or severity of disease,
§ or to the degree of disability.
Relazione con fasi di attività della malattia
Kroencke. Mult Scler 7: 237-42, 2001 Dalos. Ann Neurol 13: 573-7, 1999
§ Lesioni nel lobo temporale § Honer. Arch Neurol 44:
187-190, 1987 § Berg. Mult Scler 6: 156-62,
2000 § Zorzon. J Neurol. 248:
416-421, 2001
§ Sistema limbico § Sabatini. Biol Psychiatry 39:
970-5, 1996 § Berg. Mult Scler 6: 156-62,
2000
§ Fascicolo arcuato § Pujol. Neurology
49:1105-10, 1997
§ “Black holes” e atrofia cerebrale § Bakshi. Neuroreport. 27:
1153-8, 2000
§ Lesioni captanti gadolinio § Fassbender Arch Neurol
55: 66-72, 1998
Depressione in SM rilievi neuroradiologici
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Registrazioni in whole-cell patch clamp da neuroni striatali
Il blocco dei recettori dei glucocorticoidi ripristina la sensibilità dei recettori cannabinoidi
alterati dallo stress
Protocolli di reward naturali saccarosio 3%
TWO-BOTTLE PREFERENCE TEST (Sonnier et al, 2007) misura di gratificazione
La sPmolazione del segnale dopaminergico mediante cocaina o rinforzi naturali si oppone agli effeR dello stress sulla trasmissione endocannabinoide
CONCLUSIONI
1- I disturbi dell’umore sono di frequente osservazione in corso di malattie infiammatorie come la SM.
2 – Una complessa interazione tra le principali
citochine pro-infiammatorie, quali la IL-1 beta e il TNF-alfa, e il sistema endocannabinoide potrebbe essere alla base dei sintomi depressivi e ansiosi causati dalla neuroinfiammazione centrale.