Opzioni farmacologiche nel trattamento della depressione Obiettivi e strategie dell’assistenza riabilitativa multidisciplinare al paziente oncologico Roma , 19 settembre 2006 Opzioni farmacologiche nel trattamento della depressione Riccardo Torta SCDU Psicologia Clinica e Oncologica Dipartimenti di Oncologia e Neuroscienze ASO San Giovanni Battista ed Università di Torino

Mind Brain Body World Psychological factors Physiological and physiopathological factors Environmental factors Cultural factors Pathogenesis of depression : biopsychosocial hypothesis In the biopsychosocial hypothesis of depression brain, body, and environment influence one another and several therapeutic approaches (such as psychopharmacology or psychotherapy or social interventions) should concur to the symptomatological improvement

Increase of mortality rate in patients with somatic diseases and mood depression range of increase of mortality Hypertension Stroke Diabetes Cardiovasc. dis. Cancer 2,27 x DD 3,00 x DD 3,84 x DD 4,04 x This aspect of an increase of mortality rate in organic patients with depressive comorbidity is 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. DD 4,46 x DD Black & Markides,1999

? ADs? Depression Mortality increase smoking therapeutic compliance diet physical activity Behavioural factors HPA hyperactivity obesity hyperglycemia dyslipidemia hypertension ? Immunological alterations cellular immunity reduction Reduced HRV arrythmias What’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 related to 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 hyperaggregation ADs? Mortality increase Joynt et al, Biol Psychiatry, 54, 2003

SEROTONERGIC PATHWAYS Basal Ganglia Akatisia/agitation compulsions rostral raphe nuclei Neocortex mood Hyppocampus Limbic areas caudal raphe nuclei mood anxiety panic First of all, the term “neurotrasnmitter”, used for serotonin, norepinephrine, dopamine and so forth, is conceptually wrong because these are “transmitters” (not only “neuro”) acting on the whole body with a diffuse somatic responce to the antidepressant treatment. When we use an AD we can’t consider the vasal responce as a side effect because it is a component of the antidepressant activity. Hypothalamus Brain stem sleep,nausea, vomit sexual and eating behaviour Vessels Medulla Gut vasoconstriction vasodilatation orgasm pain motility

anxiety pain 5HT and NE dysregulation depression chronic stress It is well known that a serotonergic and noradrenergic dysregulation is present in depression, anxiety, chronic stress and pain depression chronic stress Stahl, 2002; Torta e Lacerenza, 2002; Leo, 2003

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 ?

Stress hormons and Antidepressants Treatment with antidepressants SSRI NSRI MAOI NRI Clinical improvement < CRH and AVP concentrations 1 > GR s gene expression 2 > corticosteroid brain binding 2 The adequate treatment with all antidepressant classes (TCAs,SSRIs,NRIs, NSRIs) axis induces a normalization of HPA activity that is strictly related to the direct modulating action of antidepressants on gene expression for glucocorticoid and mineralcorticoid receptors. Normalization of HPA axis activity 1- De Bellis et al, 1999 2- Reul et al.,1993

Control of genic expression (neurotrophic hypothesis) Effects of antidepressants after chronic administration nucleus Receptor BDNF NGF neurotrasnmitters release receptors down regulation effector regulation of transductional mechanisms Protein kinase Control of genic expression (neurotrophic hypothesis) An intriguing aspect concerning another effect of ADs after chronic administration is the regulation, by these drugs, of transductional mechanisms with an increased expression of neurotrophic factors, such as BDNF or NGF.

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.

? neuronal damage antidepressants Anti-cancer chemotherapy and neurotoxicity cisplatin neuronal damage neuronal store of metal vincristine taxans microtubular alterations NGF Nerve Growth Factor ? These data could explain the fact that antidepressants are useful in the treatment of neuronal damage secondary to several anticancer chemotherapies. In fact, several anticancer agents, such as platins, vincristine and taxans, induce neuronal damage throught a neuronal store of metal or microtubular alterations. According to data that demonstrate an ADs induced neurogenesis we are using ADs in oncological non depressed patients in order to exert a prophylaxis of possible neurotoxicity during chemotherapies. antidepressants neurotoxicity prophylaxis Hayakawa et al., 1998

In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways among 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.

pro-inflammatory cytokines Physiological Factors pro-inflammatory cytokines + - anti-inflammatory cytokines ADs NO/PGE2 CRH activation HPA hyperactivity IDO induction IFNa tryptophan depletion reduced 5HT availability Antidepressants can reverse, or reduce, such alterations through the increase of anti-inflammatory cytochines that counteract the activity of pro-inflammatory cytokines neurotransmitters modifications - depressive symptoms

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 response and could contribute to the development and progression of some types of cancer. Both stressors and depression are actually associated with the decreased cytotoxic T-cell and natural-killer cell activities, that affect processes such as immune surveillance of tumours.

SSRIs NARIs 5HT and NE dysregulation TCAs NaSSAs SNRIs Fluoxetine Fluvoxamine Paroxetine Sertraline Citalopram Escitalopram SSRIs NARIs Reboxetine 5HT and NE dysregulation It is well known that a serotoninergic and noradrenergic dysregulation can be present both in depression and pain But the role of these neurotransmitters in the pathogenesis of anxiety was until now not so well defined. Mirtazapine TCAs NaSSAs Amitritptyline Clomipramine SNRIs Venlafaxine Duloxetine

La scelta dello psicofarmaco: la priorità della tollerabilità paziente aspetti clinici farmaco aspetti dinamici e cinetici

Antidepressivi in oncologia es. vantaggi es. limiti TCA az.antalgica az. anticolinergica Mianserina az.antalgica leucopenia, sedazione Trazodone az. antalgica ipotensione SSRI az.antalgica collat. GE, iporessia NSRI az. antalgica collat. GE NaSSA az.antinausea astenia, sedazione NARI az. socializzante attivazione, ritenzione Benzam.sost. az.cenestesica incremento PRL SAMe trofismo mucose ev > os

Antidepressivi in oncologia es. vantaggi es. limiti TCA az.antalgica az. anticolinergica Trazodone az. antalgica ipotensione SSRI az.antalgica collat. GE, iporessia NSRI az. antalgica collat. GE, attivazione NaSSA az.antinausea astenia, sedazione NARI az. socializzante attivazione, ritenzione Benzam.sost. az.cenestesica incremento PRL SAMe trofismo mucose ev > os

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.

Mondo 2 : eventi emotivi e cognitivi Mondo 1 : eventi fisici Tiengo,1992; mod. nocicezione gate control dolore Mondo 2 : eventi emotivi e cognitivi filtro mentale

> 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

Effects of antidepressants after acute and chronic administration first antalgic effect can be indipendent from antidepressant activity first antalgic effect is reached with low doses first antalgic effect demonstrates a rapid onset reuptake inhibition The first antalgic effect of ADs can be indipendent from antidepressant activity. This first antalgic effect is reached with low doses and demonstrates a rapid onset. The following antalgic effect, that appears later, is also related to mood improvement. down regulation Receptor - later antalgic effect is also related to mood improvement

Coping Dolore QUID Mini-MAC

neurobiologia dell’analgesia da placebo Levine e Gordon Benedetti et al. effetti collaterali di depressione respiratoria naloxone blocco effetto placebo blocco recettori CCK potenziamento analgesia da placebo neurobiologia dell’analgesia da placebo Nature,1984 Pain,1997 Pain,1998 Effetto non farmacologico di un farmaco

“ 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’anima lo stesso rapporto che tra l’azione dei farmaci e le funzioni del corpo” Gorgia di Leontini (Elogio di Elena)