Michele Mattia Manno, 7 maggio 2015 Antipsicotici Michele Mattia Manno, 7 maggio 2015

Obbiettivi Schizofrenia Psicosi debuttante Antipsicotici Leponex Indicazioni NL in geriatria pro e contro Prescrizioni dei NL da parte M di F: nelle domande

Schizophreniform disorder DSM-IV Diagnosis Schizophrenia Symptoms > 6 months Schizophreniform disorder Symptoms 1 month - 6 months Brief psychotic disorder Symptoms 1 day - 1 month

Prognosis of Schizophrenia 10-20% continuous hospitalization < 30% recovery = symptom-free for 5 years 60% continued problems in living/episodic periods

Etiology Hereditary Influences may account for 10% of schizophrenia cases Prenatal Biological Trauma 5-10% cases of schizophrenia Perinatal biological trauma Diathesis - Stress Model

MENTAL ILLNESSES Environmental factors Maturational factors Neuronal connectivity Neurotransmitters Receptors/drug targets

Environmental Factors Schizophrenia Environmental Factors Exposure to infections Toxic/Traumatic ( in utero) Insults Schizophrenia ALTERATIONS IN NEURODEVELOPMENT Autoimmunity Stress during gestation or early in childhood/adolescence

STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA Schizophrenics show deficits in tasks involving prefrontal cortex or those requiring working memory Prefrontal cortical thickness is reduced 5-10%, neuron size is down, but no change in neuron number Synaptic connectivity is reduced Medial dorsal thalamus shows 30% reduction in neuron number Prefrontal cortex receives fewer projections from the thalamus Hippocampus shows altered cytoarchitecture

IL SIGNIFICATO DI « PSICOSI » LA TRASFORMAZIONE DELLA REALTA’ (sintomi positivi) DELIRI ALLUCINAZIONE LA DISORGANIZZAZIONE L’IMPOVERIMENTO LA PERDITA DI INSIGHT ALTERAZIONI COGNITIVE – DESTRUTTURAZIONE IDEATIVA E COMPORTAMENTALE APATIA – ABULIA - ALOGIA DECADIMENTO DELLA CRITICA – MANCANZA DELLA COSCIENZA DI MALATTIA

Les cinq dimensions de la schizophrénie Implication de la dopamine, sérotonine et glutamate… Stephen M. Stahl Flammarion 2002

Schizophrenia - symptoms Positive Symptoms Hallucinations Delusions (bizarre, persecutory) Disorganized Thought Perception disturbances Inappropriate emotions Negative Symptoms Blunted emotions Anhedonia Lack of feeling FUNCTION Mood Symptoms Loss of motivation Social withdrawal Insight Demoralization Suicide Cognition New Learning Memory

le 4 A di Bleuler 1) autismo 2) ambivalenza 3) affettività disturbata 4) allentamento dei nessi associativi

Psicosi debuttante alterazioni del comportamento, isolamento e impairment sociale, alterazioni dell’interazione con i pari ritardi dello sviluppo, difficoltà motorie anomalie del linguaggio difficoltà di apprendimento,

Psicosi debuttante alterazioni dele abilità di problem solving idee di riferimento riduzione della capacità di gestire le normali attività quotidiane, l’avolizione, l’aggressività un’elevata ostilità

Sintomi prodromici e premorbosi della schizofrenia ad esordio precoce Sintomi prodromici e premorbosi della schizofrenia ad esordio precoce. Prodromal and premorbid symptoms of early-onset schizophrenia (da Alaghband-Rad et al., 1995 34; McClellan et al., 2002 51; McGorry et al., 2002 50; Schaffer e Ross, 2002 46). Sintomi prodromici Sintomi premorbosi Sintomi psicotici attenuati Anomalie precoci motorie/del linguaggio Comportamenti bizzarri Scarso adattamento sociale premorboso Ritiro sociale difficoltà di socializzazione Improvviso deterioramento del funzionamento premorboso Comportamenti oppositivi/aggressivi Storia di difficoltà attentive (che non rispondono agli psicostimolanti) deficit attentivi e difficoltà di apprendimento Appiattimento affettivo Fluttuazioni dell’umore

antipsicotico ideale Efficacia su: Deliri Allucinazioni Disorganizzazione Sintomi negativi Buon rapporto rischio/beneficio per effetti collaterali somatici Non induzione di: sedazione stabile depressione del tono dell’umore deficit cognitivo Non induzione di sintomi extra-piramidali.

Antipsicotici The terms “first-generation” and “second- generation” antipsychotics, have been in use since 2004. The second-generation antipsychotics are recommended in various guidelines as first-line treatment in view of their better neurological tolerability, greater efficacy on negative, cognitive, and depressive symptoms. 143.14-LAT

ANTIPSYCHOTICS “Typical”, conventional, traditional neuroleptics, major tranquilizers Modeled on D2 antagonism EPS/TD “Atypical”, novel, 2nd generation Modeled on 5-HT2/D2 antagonism Less EPS, prolactin effects Weight gain, sedation, diabetes

Antipsicotici: tolerability Concerning tolerability, whereas second-generation antipsychotics induced much weaker neurological side effects, they induced metabolic (weight gain, hyperglycemia, anddyslipidemia) and cardiac side effects (QT prolongation) requiring regular monitoring. Differences were also found among the second-generation antipsychotics. 143.14-LAT

Antipsicotici: tolerability Also, concerning metabolic side effects, olanzapine and clozapine produced more weight gain than all the other second-generation antipsychotics, and olanzapine produced a higher rise in cholesterol than aripiprazole, risperidone, and ziprasidone. Overall, these recent data confirm that second-generation antipsychotics are not a homogeneous group. 143.14-LAT

antipsicotici La differenza tra AP di prima e seconda generazione è l’ occupazione recettoriale. La dose terapeutica degli AP di II generazione è più bassa rispetto agli AP di I generazione, per cui l’ occupazione recettoriale è inferiore all’ 80-85%, soglia di comparsa degli EPS. Gli effetti collaterali possono essere divisi in due classi temporali: precoci e tardivi.

Dopamine Receptors Occupancy—therapeutic vs. side effects At therapeutic doses the “classical” antipsychotics occupy >75% of dopamine D-2 receptors. 85% occupancy needed to get extrapyramidal side effects. Clozapine, the “atypical”, blocks only 35% D-2 receptors at therapeutic doses.

Introduction to Atypical Antipsychotics (2 of 4) By 2001, 95.9 percent of antipsychotics prescribed to new users were of the atypical class. Aripiprazole (Abilify®) Asenapine (Sycrest®) Clozapine (Leponex®,) Iloperidone (Fanapt®) Olanzapine (Zyprexa®) Paliperidone (Invega®) Quetiapine (Seroquel®) Risperidone (Risperdal®) Ziprasidone (Geodon®) Lurasidone (Latuda) Sertindolo (Serdolect) Amisulpiride (Solian) Introduction to Atypical Antipsychotics (2 of 4) As of the date of this review, nine second-generation, atypical antipsychotic drugs have been approved by the U.S. Food and Drug Administration (FDA). Aripiprazole (Abilify®) Asenapine (Saphris®) Clozapine (Clozaril®, FazaClo®) Iloperidone (Fanapt®) Olanzapine (Zyprexa®) Paliperidone (Invega®) Quetiapine (Seroquel®) Risperidone (Risperdal®) Ziprasidone (Geodon®) Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm. Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

Atypical antipsychotics MARTA (multi acting receptor targeted agents) clozapine, olanzapine, quetiapine SDA (serotonin-dopamine antagonists) risperidone, ziprasidone, sertindole Selective D2/D3 antagonists sulpiride, amisulpiride

Off-label indications of atypical antipsychotics Dementia Major depressive disorder (MDD) Obsessive-compulsive disorder (OCD) Borderline personality disorder (BPD) Post-traumatic stress disorder (PTSD) Substance abuse Eating disorders Anxiety Insomnia Summary of Studies Included in the Comparative Effectiveness Review (2 of 2) Off-label indications of atypical antipsychotics that have been studied and reported in the clinical literature are: - Dementia - Major depressive disorder (MDD) - Obsessive-compulsive disorder (OCD) - Borderline personality disorder (BPD) - Post-traumatic stress disorder (PTSD) - Substance abuse - Eating disorders - Anxiety - Insomnia Reference: Maglione M, Ruelaz Maher A, Hu J, et al. Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Review No. 43 (Prepared by the Southern California RAND Evidence-based Practice Center under Contract No. HHSA 290-2007-10062-I). Rockville, MD: Agency for Healthcare Research and Quality; September 2011. AHRQ Publication No. 11(12)-EHC087-EF. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm. Maglione M, Ruelaz Maher A, Hu J, et al. Comparative Effectiveness Review No. 43. Available at www.effectivehealthcare.ahrq.gov/offlabelantipsych.cfm.

Neurological Side Effects of antipsychotics REACTION FEATURES TIME OF MAXIMAL RISK PROPOSED MECHANISM TREATMENT   Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria 1 to 5 days Unknown Antiparkinsonian agents are diagnostic and curative Akathisia Motor restlessness; not anxiety or "agitation" 5 to 60 days Reduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may help Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait 5 to 30 days Antagonism of dopamine Antiparkinsonian agents helpful Neuroleptic malignant syndrome Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal Weeks; can persist for days after stopping neuroleptic Antagonism of dopamine may contribute Stop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effective Perioral tremor ("rabbit" syndrome) Perioral tremor (may be a late variant of parkinsonism) After months or years of treatment Antiparkinsonian agents often help Tardive dyskinesia Oral-facial dyskinesia; widespread choreoathetosis or dystonia After months or years of treatment (worse on withdrawal) Excess function of dopamine hypothesized Prevention crucial; treatment unsatisfactory a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

Profili di legame ai recettori degli antipsicotici in vitro Antipsicotico Antagonismo Antag. D2 AP D2 5-HT1A 5-HT2A 5-HT2C 5-HT7 α1 M1 H1 Lurasidone +++ + ++++ ++ Aripiprazolo Olanzapina Quetiapina Risperidone Affinità di legame: ++++ molto elevata +++ elevata ++ moderatamente elevata + bassa AP: agonista parziale Adapted from Stahl SM. Stahl’s essential psychopharmacology. 4th ed. New York, NY: Cambridge University Press, 2013. 280.13-LUR

Affinités relatives pour divers récepteurs et effets cliniques possibles Arip. Asén. Cloz. Olan. Quét. Risp./ Pali.* Zip. Effets cliniques possibles de l’activité au niveau des récepteurs† D2 +++++ ++++ ++ +++ Efficacité contre les symptômes positifs, symptômes extrapyramidaux, effets endocriniens 5-HT2A Efficacité contre les symptômes négatifs, réduction des symptômes extrapyramidaux 5-HT2C + Amélioration du sommeil et de la cognition, gain pondéral 5-HT1A Court terme : agitation plus probable Long terme : effet antidépresseur et anxiolytique α1-adrénergique ++++/ +++ Hypotension orthostatique Muscarinique M1 ̶ ─ Effets indésirables anticholinergiques (par ex., déficience cognitive); effets périphériques (par ex., sécheresse de la bouche, rétention urinaire) Histaminergique H1 Sédation, gain pondéral Notes du conférencier  : En extrapolant les données fournies sur la diapositive précédente, on pourrait être en mesure de prédire certains des effets que les différents antipsychotiques atypiques sont susceptibles d’exercer sur le plan clinique. (Notons toutefois que l’affinité de liaison aux récepteurs observée in vitro ne présage pas toujours de son effet clinique.) L’affinité relative des différents antipsychotiques atypiques pour les récepteurs 5-HT pourrait être en corrélation avec l’efficacité de ces agents contre les symptômes positifs, négatifs, anxieux et dépressifs, de même qu’avec la fréquence des symptômes extrapyramidaux qui leur est associée. Une affinité pour les récepteurs α1-adrénergiques pourrait laisser entrevoir une possible hypotension orthostatique. L’affinité pour les récepteurs muscariniques M1 permet de prédire une propension à provoquer des effets indésirables anticholinergiques, y compris un dysfonctionnement cognitif et des troubles gastro-intestinaux. Une affinité pour les récepteurs histaminergiques H1 pourrait être associée à un risque de sédation et de gain pondéral. Références : Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29-39. Schmidt AW, Lebel LA, Howard HR Jr, Zorn SH. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol. 2001;425:197-201. Shapiro DA, Renock S, Arrington E, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology. 2003;28 : 1400-1411. Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. J Clin Psychiatry. 2003;64(suppl. 19):6-12. Légende : Très forte affinité (de 0,1 à 1,0) = +++++; Forte affinité (de 1,0 à 10) = ++++; Affinité modérée (de 10 à 100) = +++; Affinité modérément faible (de 100 à 1000) = ++; Faible affinité (de 1000 à 10 000) = +; Affinité négligeable (plus de 10 000) = - . Richelson et al. Life Sci 2000;.68:29-39. Schmidt AW et al. Eur J Pharmacol. 2001;425:197-201. Shapiro et al. Neuropsychopharmacology 2003;28:1400-1411. Stahl SM et al. J Clin Psychiatry. 2003;64(suppl. 19):6-12. * Le tableau d’affinité de la palipéridone est identique, sauf pour les récepteurs α1-adrénergique pour lesquels son affinité est plus faible. † Il se peut que les observations faites in vitro ne correspondent pas aux résultats obtenus sur le plan clinique. 37

Lurasidone low affinity for α1 and α2C-adrenergic and 5HT2C serotonin receptors, and no affinity for histaminergic H1 or muscarinic M1 receptors, suggesting a better tolerability profile than the other second-generation antipsychotics. Lurasidone differs from the other second-generation antipsychotics by having a good tolerability profile, in particular for cardiometabolic tolerability. However, it seems to have a significant although moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia at the start of treatment. 143.14-LAT

ANTIPSICOTICI TRADIZIONALI O “TIPICI” Efficacia sui sintomi positivi Poco o non efficaci sui sintomi negativi, cognitivi e depressivi Elevati rischi di effetti collaterali, talora gravi e persistenti Effetti extrapiramidali (EPS) Elevata incidenza (5%) e prevalenza (20%) di discinesia tardiva (DT) Effetti secondari a iperprolattinemia (IPERPRL) (60-95%)

Effetti EPS precoci Effetto collaterale Fattori di rischio Tempo di insorgenza dall’ inizio della tp Discinesia tardiva Discinesie coreo-atetoidi muscoli bocca, lingua, arti, tronco giovane età, alti dosaggi, sesso femminile, diagnosi di disturbi affettivi mesi o anni Acatisia Irrequietezza motoria associata a tensione emotiva   5-60 giorni Parkinsonismo Bradicinesia, rigidità, iporeflessia posturale tarda età sesso femminile 5-30 giorni

Effetti EPS tardivi Effetto collaterale Fattori di rischio Tempo di insorgenza dall’ inizio della tp Distonia acuta Spasmo muscoli lingua, volto, collo, tronco giovane età sesso maschile 1-5 giorni Distonia tardiva Spasmi muscoli arti, tronco, collo   mesi o anni Sindrome del coniglio Tremore parkinsoniano labbra e muscoli periorali tarda età

SINTOMI DA IPERPROLATTINEMIA UOMO DONNA A breve termine · Perdita libido · Impotenza · Disturbi di eiaculazione · Ridotta spermatogenesi · Ginecomastia · Galattorrea (raro) A lungo termine ·Osteoporosi da carenza di testosterone · Aumento ponderale ·Alterazione dell’umore (?) Ciclo mestruale ·Accorciamento fase luteinica · Oligo-amenorrea ·Anovulazione Seno · Tensione mammaria · Galattorea Funzione sessuale · Riduzione della libido · Disfunzione orgasmica Cutanei · Acne · Irsutismo · Osteoporosi da carenza di estrogeni · Cancro a seno e endometrio (?) · Disturbi cardiovascolari · Alterazioni dell’umore (?)

Antipsicotici, prolungamento del QT ed eventi aritmici insorgenza di aritmie ventricolari quali la torsione di punta (TdP) la fibrillazione, che possono condurre ad arresto cardiaco e morte improvvisa. Il prolungamento dell’intervallo QT, corretto per la frequenza cardiaca QTc, rappresenta attualmente il principale marker surrogato di rischio per TdP.

  aloperidolo-droperidolo pimozide amisulpride-bromperidolo-clorpromazina clotiapina-clozapina-flufenazina-quetiapina levomepromazina-risperidone-sulpride-olanzapina-aripriprazolo levosulpride-perfenazina-promazina-tiapride Controindicazioni · Malattie cardiache clinicamente significative (recente IMA,insufficienza cardiaca scompensata) · Prolungamento QTc · Soggetti con storia familiare di aritmia o torsione di punta · Ipopotassiemia non corretta · Concomitante uso di farmaci che prolungano QTc Avvertenze speciali e Precauzioni d’ uso · Usare con cautela nei pazienti con malattie cardiovascolari o con storia familiare di prolungamento QT. · Effettuare ECG di base prima di iniziare il trattamento. · Effettuare monitoraggio ECG nel corso della terapia sulle basi delle condizioni cliniche del paziente. · Ridurre il dosaggio se si osserva prolungamento QT e interrompere se il QTc è > 500ms. · Controllo periodico elettroliti. · Evitare terapia concomitante con altri neurolettici. · Usare con cautela nei paz. con malattie cardiovascolari o con storia familiare di prolungamento QT.

Effetti collaterali degli antipsicotici ANTIPSICOTICI TIPICI: ALTRI EFFETTI COLLATERALI Sindrome Maligna da Neurolettici Disturbi SNA Aumento di peso Soglia convulsivante più bassa Disturbi cardiaci Fotosensibilizzazione

Bassa incidenza di effetti collaterali neurologici CARATTERISTICHE CLINICHE DELLA TERAPIA CON CLOZAPINA Bassa incidenza di effetti collaterali neurologici Azione terapeutica sui sintomi positivi e negativi Efficacia nel 30-40% di pazienti schizofrenici farmacoresistenti Rischio di agranulocitosi nello 0.5-1% dei pazienti trattati (rischio aumentato con carbamazepine) Non induce iperprolattinemia

Clozapine Extrapyramidal side effects are minimal May help treat tarditive dyskinesia Still shows orthostatic hypotension effects, sedation, weight gain, increased heart rate Increased risk for seizures (2-3%) Interactions with SSRIs and valproic acid increase Clozapine levels and risks

ATYPICAL ANTIPSYCHOTIC USE IN PATIENTS WITH DEMENTIA: MANAGING SAFETY CONCERNS

Farmaci per specifici cluster di BPSD Antipsicotici Benzodiazepine ‘Agitazione psicomotoria’ ‘Aggressività’ Antipsicotici AChE-inibitori ‘Apatia’ Antidepressivi benzodiazepine ‘Depressione’ Ansia Antipsicotici AChE-inibitori ‘Psicosi’ Adattato da McShane R. Int Psychogeriatr 2000; 12(Suppl 1): 147–54

The neuropsychiatric symptoms (NPS) of dementia NPS (e.g., delusions, depression, agitation) affect up to 97% of people with dementia over the course of their illness. No atypical antipsychotic is FDA-approved for the treatment of any NPS in dementia. The decision to initiate an atypical antipsychotic in the elderly with dementia is not one to be taken lightly. Large scale meta-analyses of clinical trials have consistently demonstrated a 1.5–1.7 times increased risk of mortality with their use in dementia. All atypical antipsychotics carry a black box warning from the FDA about this risk, and a similar warning applies to conventional antipsychotics. Atypical antipsychotics are also linked to a 2–3 fold higher risk of cerebrovascular events (CVAE) (absolute risk of approximately 1%.)

The 2012 American Geriatric Society (AGS) Beers consensus criteria for safe medication use in the elderly recommend avoiding antipsychotics to treat NPS of dementia due to the increased mortality and CVAE risk “unless nonpharmacological options have failed and patient is threat to self or others”. Additional adverse effects include cardiovascular and metabolic effects, extrapyramidal symptoms, cognitive worsening, infections and falls.

Cerebrovascular events In 2003, the FDA warned of an association between risperidone and cerebrovascular events (CVAE), including stroke, in elderly patients with dementia. Additional clinical trials of risperidone, olanzapine, and aripiprazole show similar risks, and the FDA warning now applies to all atypical neuroleptics. The risk for CVAE appears to be highest during the initial weeks of treatment and may revert to background level after 3 months. Atypical and conventional antipsychotics are associated with a similarly increased risk for CVAE.

ADERENZA AL TRATTAMENTO 50 e 60% psicosi 35% disordini affettivi bipolari. Cramer, Rosenheck. Compliance with medication Regimens for mental and physical disorders. Psychiatr. Serv 1998, 49:196-201.

Domande? 143.14-LAT