Presentazione sul tema: "Opzioni farmacologiche nel trattamento della depressione"— Transcript della presentazione:
1 Opzioni farmacologiche nel trattamento della depressione Obiettivi e strategie dell’assistenza riabilitativa multidisciplinareal paziente oncologicoRoma , 19 settembre 2006Opzioni farmacologichenel trattamento della depressioneRiccardo Torta SCDU Psicologia Clinica e OncologicaDipartimenti di Oncologia e Neuroscienze ASO San Giovanni Battista ed Università di Torino
2 MindBrainBodyWorldPsychological factorsPhysiological and physiopathological factorsEnvironmental factorsCultural factorsPathogenesis of depression : biopsychosocial hypothesisIn the biopsychosocial hypothesis of depressionbrain, body, and environment influence one anotherand several therapeutic approaches(such as psychopharmacology or psychotherapy or social interventions)should concur to the symptomatological improvement
3 Increase of mortality rate in patients with somatic diseases and mood depression range of increase of mortalityHypertensionStrokeDiabetesCardiovasc. dis.Cancer2,27 xDD3,00 xDD3,84 xDD4,04 xThis aspect of an increase of mortality rate in organic patients with depressive comorbidityis reported by several trials (this one from Black and Markides in a mexican population)in different pathologies (hypertension, stroke, diabetes, cardiovascular diseases and cancer)with a range of increase of mortality up to 4 times.DD4,46 xDDBlack & Markides,1999
4 ? ADs? Depression Mortality increase smoking therapeutic compliance dietphysical activityBehavioural factorsHPA hyperactivityobesityhyperglycemiadyslipidemiahypertension?Immunological alterationscellular immunityreductionReduced HRVarrythmiasWhat’s the relation between mood depression and mortality?Until few years ago we used to consider only behavioural aspects of depression,such as smoking increase, reduction of therapeutic compliance, bad diet and poor physical activity.In the last years it was well known that mood depression is also relatedto a Hypotalamus Pituitary Adrenal hyperactivity, with an increased release of stress hormones.This situation is linked to obesity, metabolic alterations and hypertension.Another risk factor for mortality in depressed patient, for example after MI,is a reduced Heart Rate Variability that means the prevalence of the sympathetic tone on parasympathetic one, with lower control on ventricular fibrillation.It is also well known that increased platelets aggregation is observed during mood depression:because platelets present an upregulation of surface receptors secondary to the serotonergic reduction.The bet is: ADs act on these somatic alterations directly ,throught mood improvement or both?PLT’s hyperaggregationADs?Mortality increaseJoynt et al, Biol Psychiatry, 54, 2003
6 SEROTONERGIC PATHWAYS Basal GangliaAkatisia/agitation compulsionsrostral raphe nucleiNeocortexmoodHyppocampusLimbic areascaudal raphe nucleimoodanxietypanicFirst of all, the term “neurotrasnmitter”, used for serotonin, norepinephrine, dopamine and so forth,is conceptually wrongbecause these are “transmitters” (not only “neuro”) acting on the whole bodywith a diffuse somatic responce to the antidepressant treatment.When we use an AD we can’t consider the vasal responce as a side effectbecause it is a component of the antidepressant activity.HypothalamusBrain stemsleep,nausea, vomitsexual and eating behaviourVesselsMedullaGutvasoconstriction vasodilatationorgasm painmotility
7 anxiety pain 5HT and NE dysregulation depression chronic stress It is well known that a serotonergic and noradrenergic dysregulationis present in depression, anxiety, chronic stress and paindepressionchronic stressStahl, 2002; Torta e Lacerenza, 2002; Leo, 2003
8 A patient with mood depression and/or a chronic stress demonstrates a hyperfunction of hypotalamus-pituitary-adrenal axis (HPA).The hypersecretion of CRF stimulates an increased release of ACTH,that, in its turn, induces an excess of cortisol.Stress hormones, in the long term, cause a neuronal and glial apoptosis in hippocampus.How ADs act on this dysregulation ?
9 Stress hormons and Antidepressants Treatment with antidepressantsSSRINSRIMAOINRIClinical improvement< CRH and AVP concentrations 1> GR s gene expression 2> corticosteroid brain binding 2The adequate treatment with all antidepressant classes (TCAs,SSRIs,NRIs, NSRIs) axisinduces a normalization of HPA activitythat is strictly related to the direct modulating action of antidepressantson gene expression for glucocorticoid and mineralcorticoid receptors.Normalization of HPA axis activity1- De Bellis et al, 19992- Reul et al.,1993
10 Control of genic expression (neurotrophic hypothesis) Effects of antidepressants after chronic administrationnucleusReceptorBDNFNGFneurotrasnmitters releasereceptors down regulationeffectorregulation of transductional mechanismsProtein kinaseControl of genic expression(neurotrophic hypothesis)An intriguing aspect concerning another effect of ADs after chronic administrationis the regulation, by these drugs, of transductional mechanismswith an increased expression of neurotrophic factors, such as BDNF or NGF.
11 More recently some studies investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat,using the thymidine analog bromodeoxyuridine (BrdU)as a marker for dividing cells.
12 ? neuronal damage antidepressants Anti-cancer chemotherapy and neurotoxicitycisplatinneuronal damageneuronal store of metalvincristine taxansmicrotubular alterationsNGFNerve Growth Factor?These data could explain the fact that antidepressants are usefulin the treatment of neuronal damage secondary to several anticancer chemotherapies.In fact, several anticancer agents, such as platins, vincristine and taxans,induce neuronal damagethrought a neuronal store of metal or microtubular alterations.According to data that demonstrate an ADs induced neurogenesiswe are using ADs in oncological non depressed patientsin order to exert a prophylaxis of possible neurotoxicity during chemotherapies.antidepressantsneurotoxicityprophylaxisHayakawa et al., 1998
13 In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathwaysamong nervous, endocrine and immune systems.Today we know that proinflammatory cytokines,such as interleukin (IL)-1, tumor necrosis factor (TNF)-a and interferon (IFN)-a,can elicit a major depression, during a treatment for cancer, multiple sclerosis or chronic hepatitis.
14 pro-inflammatory cytokines Physiological Factorspro-inflammatory cytokines+-anti-inflammatory cytokinesADsNO/PGE2CRH activationHPA hyperactivityIDO inductionIFNatryptophan depletionreduced 5HT availabilityAntidepressants can reverse, or reduce, such alterationsthrough the increase of anti-inflammatory cytochinesthat counteract the activity of pro-inflammatory cytokinesneurotransmitters modifications-depressive symptoms
15 The persistent activation of the HPA axis, Another very important aspect concerns the relations among stress, depression and immune system.The persistent activation of the HPA axis,both present in chronic stress and in mood depression,probably impairs the immune responseand could contribute to the development and progression of some types of cancer.Both stressors and depression are actually associatedwith the decreased cytotoxic T-cell and natural-killer cell activities,that affect processes such as immune surveillance of tumours.
16 SSRIs NARIs 5HT and NE dysregulation TCAs NaSSAs SNRIs FluoxetineFluvoxamineParoxetineSertralineCitalopramEscitalopramSSRIsNARIsReboxetine5HT and NEdysregulationIt is well known that a serotoninergic and noradrenergic dysregulationcan be present both in depression and painBut the role of these neurotransmitters in the pathogenesis of anxietywas until now not so well defined.MirtazapineTCAsNaSSAsAmitritptylineClomipramineSNRIsVenlafaxineDuloxetine
17 La scelta dello psicofarmaco: la priorità della tollerabilità pazienteaspetti clinicifarmacoaspetti dinamici e cinetici
20 Antidepressivi e dolore In ambito psiconcologico la psicofarmacoterapia si colloca in un contesto integrato con la psicoterapia, assumendo talora importanza prioritaria ( ad esempio nella gestione delle urgenze), talaltra ponendosi in secondo piano rispetto al sostegno psicologico come intervento contingente, finalizzato al superamento della crisi.
21 Mondo 2 : eventi emotivi e cognitivi Mondo 1 : eventi fisiciTiengo,1992; mod.nocicezionegate controldoloreMondo 2 : eventi emotivi e cognitivifiltro mentale
22 > attivazione cingolo anteriore e cortex somato-sensoriale variabilità interindividuale nella percezione del dolore (Coghill et al., 2003)(Coghill et al., 2003)alta sensibilità :> attivazione cingolo anteriore e cortex somato-sensoriale
23 Effects of antidepressants after acute and chronic administration first antalgic effect can be indipendent from antidepressant activityfirst antalgic effect is reached with low dosesfirst antalgic effect demonstrates a rapid onsetreuptake inhibitionThe first antalgic effect of ADs can be indipendent from antidepressant activity.This first antalgic effect is reached with low dosesand demonstrates a rapid onset.The following antalgic effect, that appears later, is also related to mood improvement.down regulationReceptor- later antalgic effect is also related to mood improvement
25 neurobiologia dell’analgesia da placebo Levine e GordonBenedetti et al.effetti collaterali didepressione respiratorianaloxoneblocco effetto placeboblocco recettori CCKpotenziamento analgesia da placeboneurobiologia dell’analgesia da placeboNature,1984Pain,1997Pain,1998Effetto non farmacologico di un farmaco
26 “ La parola è un gran dominatore... riesce infatti a calmare la paura, ad eliminare il dolore...C’è, tra la potenza della parola e la funzione dell’animalo stesso rapportoche tra l’azione dei farmaci e le funzioni del corpo”Gorgia di Leontini(Elogio di Elena)