Universit degli studi di Genova Facolt di Medicina

Università degli studi di Genova Facoltà di Medicina e Chirurgia Dipartimento di Neuroscienze Clinica Psichiatrica Dai Sintomi Prodromici al Primo Episodio Quali Trattamenti Mario Amore

Fattori di rischio ambientali per psicosi lungo il corso dello sviluppo (Broome, Murray, 2005) eventi pre e perinatali Avversità sociali Geni dei neurotrasmettitori es. COMT Geni di suscettibilità, Copy number variations Fattori precoci Disregolazione Dopamina Ansia sociale, ideazione psicotica, depressione Lievi deficit motori, cognitivi e sociali 0 Droghe es cannabis 5 10 Età (anni) 15 20 Fattori prossimali P s i c o s i esordio

Duration of untreated psycoses “First Episode” Schizophrenia: Definitions and Concepts C B Normal Psychosis Any Symptom D A “Prodromal period” A The patient’s symptoms do not meet threshold criteria for psychosis but may Include attenuated positive symptoms B The onset of acute psychotic symptoms occur when the patient has clearly Defined psychotic symptoms. Intervention during this time is not considered a Prodromal intervention C The duration of UP represent the gap between the onset of acute symptoms And initial clinical presentation (D), wich often is triggered by an external event That is the result of worsening behavior (Weiden PJ, 2009)

‘At-risk mental state’ The Ultra-high risk approach n Melbourne Criteria n n n Subtreshold positive symptoms that are not severe or persistent enough to meet criteria sufficient for a diagnosis of a DSM IV or ICD-10 A family history of psychotic disorder or schizotypal disorder in a first degree relative plus a significant, persistent but nonspecific decline in psychosocial functioning within the past year or so Brief and Limited Intermittent Psychotic Symptoms n Based on these criteria, the rate of transition to psychosis is 41% within a one-year follow-up period

Ultra high risk criteria Nelson et al, 2011

Revised proposed DSM-5 criteria for APS syndrome

Revised proposed DSM-5 criteria for APS syndrome Sintomi psicotici attenuati: Meno severi, più transitori, insight relativamente conservato, cambiamento notato da paziente e familiari MA «Non progredita fino a completa gravità psicotica» DELIRI ATTENUATI ALLUCINAZIONI ATTENUATE COMUNICAZIONE DISORGANIZZATA Convinzioni poco organizzate, meno rigide, possibile grado di elaborazione. Es. idee persecutorie di riferimento, idee di superiorità Suoni o immagini indefinite, vissuti come inusuali o misteriose Scetticismo del paziente circa la loro realtà Eloquio bizzarro, poco focalizzato, contorto ma ancora comprensibile, anche dopo richiesta di chiarificazione al pz.

A substantial proportion of individuals with APS do not go on to develop major psychopathology TASSI DI TRANSIZIONE A PSICOSI CONCLAMATA: 18% after 6 months of follow-up, 22% (95% CI, 16. 6%– 27. 8%) after 1 year, 29% (95% CI, 23. 3%– 35. 7%) after 2 years, and 36% (95% CI, 29. 6%– 42. 5%) after 3 years. Other PROBLEMATIC ISSUES: -The majority of current APS have psychiatric comorbidity - unclear if APS represents a trait or state vulnerability - potential stigma, discrimination and inappropriate antipsychotic utilization in APS

The UHR Groups Transition to psychosis 1. UHR patients who have experienced BLIPS have the highest risk, followed by subjects with APS, followed by those who met the trait criterion only 2. BLIPS patients require a different, or a more intensive form of treatment than other UHR patients 3. The effect of different intervention strategies (Antipsychotics, neuroprotective agents, and psychosocial interventions) on different UHR groups remains to be evaluated

Sintomi di Base �Compromissione autopercepita di spinta, emozioni, percezioni, propriocettività, pensiero, linguaggio, pianificazione delle attività �Esperienze elementari, acaratteristiche, confinate alla sfera soggettiva e vissute come disturbi

Sintomi di Base I sintomi di base sono considerati la più immediata manifestazione fenomenica di un disturbo fondamentale situato a livello transfenomenico, non esperito dal soggetto perché attivo al di fuori del suo campo di coscienza. - Disturbo della ricezione e della elaborazione delle informazioni - alterazione biologica ulteriormente sottostante, situata a livello prefenomenico, la quale corrisponderebbe a una disfunzione neurofisiologica e neurotrasmettitoriale a livello del lobo limbico.

I Sottodomini dei sintomi di Base 1. Diminished affectivity (globale deflazione del potenziale affettivo), 2. Disturbed contact (difficoltà e imbarazzo soggettivamente vissuto nei contesti sociali e interpersonali). 3. Perplexity (alterata articolazione o comprensione intuitiva dei significati), 4. Cognitive disorder (esperienza della ridotta fluidità dei processi cognitivi), 5. Self-disorder (anomalie dell’esperienza del Sé), 6. Coenesthesias (anomalie dell’esperienza della corporeità) 7. Perceptual disorder (distorsioni percettive).

Sintomi di Base LIVELLO FENOMENICO SINTOMI PSICOTICI SINTOMI DI BASE LIVELLO TRANSFENOMENICO DISTURBO DELLA PROCESSAZIONE DELLE INFORMAZIONI (Grundstörung) LIVELLO PREFENOMENICO ALTERAZIONI NEUROBIOLOGICHE (Neurofisiologicheneurotrasmettitoriali)

Modello dei Sintomi di Base Gli schizofrenici nel decorso della loro malattia presentano: Ø stadi di base caratterizzati da SB e da mantenimento dell’insight, della capacità di esperire e comunicare i loro deficit e di elaborare meccanismi di coping e di adattamento Ø Continuum fenomenologico di Erlebnisse intermedi progressivamente più caratteristici, che connette i Sintomi di Base ai sintomi diagnostici della schizofrenia Ø non destrutturazione della personalità, ma una personalità limitata nelle sue potenzialità e nella sua efficienza Ø I sintomi schizofrenici positivi costituiscono quindi il punto di arrivo di un percorso psicopatologico, a partenza da disturbi elementari, punteggiato da definite transizioni fenomeniche

Item C 1. 17 BSABS Subject-Zentrismus • Subapophanic Self-centrality: vissuto elusivo e transitorio di autoriferimento con ripristino immediato della capacità di attuare la svolta copernicana (la svolta tolemaica rimane sospesa tra «sentimento» di autoriferimento e perplessa negazione di esso) • Overt delusional Self-centrality: irreversibile perdita della capacità di cambiare il sistema di riferimento

L’esordio in un’ottica fenomenologica «TREMA» : Irrigidimento della capacità di situarsi prospetticamente, di trascendersi; “l’impossibilità del passaggio è sentita come barriera” e l’intero campo psichico è percorso da uno stato di allarme immanente e indefinibile. «APOFANIA» dispiegarsi totalizzante del dispositivo antropologico della rivelazione «ANASTROFE» : Scivolamento in un diffuso e incombente erlebnis di autoriferimento (suscettibile di regredire col ripristino della capacità di decentrarsi). “Nella sua psicosi lo schizofrenico ha perso la possibilità di trascendersi… qualunque sia l’oggetto del suo sguardo, in qualunque direzione vada lo strale della sua intenzionalità, quell’oggetto lo “riguarda»

North American Prodrome Longitudinal Study Addington et al, 2011 225 helpseeking individuals who met attenuated positive symptom rish criteria 2. 5 year period 35% developed a psychotic illness 24% remitted their attenuated symptoms 20% retained attenuated positive symptoms at lower levels of severity 21% received an AP drug in the prodromal phase

• The intuitive appeal to early intervention must be offset by the risks inherent in such treatments as well as the concern of treating patients who might not develop schizophrenia AT RISK MENTAL STATE PRODROMAL PHASE n ULTRA HIGH RISK (UHR) Patients identified as prodromal for schizophrenia do not necessarily go on to have schizofrenia (Weiden PJ, 2009)

Differences between the ultra-high-risk (UHR) and controls (HC) group Mechelli et al, 2011

Differences between ultra-high-risk (UHR) individuals who did (UHR-T) and did not (UHR-NT) develop psychosis Mechelli et al, 2011

Conclusions The UHR group: less regional gray matter volume in 3 areas of the frontal cortex: the media orbital gyrus and the gyrus rectus bilaterally and th right anterior cingulate gyrus Individuals who developed psychosis: Reductions in the anterior part of the left parahippocampal volume and alterations in parahippocampal function in high-risk individuals relative to controls The volumetric differences observed between UHR-T and UHRNTcould be neurobiological markers of an especially increased vulnerability to psychosis or as early manifestations of a neuropathologic process underlying the transition to psychosis Mechelli et al, 2011

Early and tardive deficit of gray matter Severe parietal, motor, and diffuse frontal loss has already occurred and subsequently continue, the temporal and dorsolateral prefrontal loss characteristic of adult schizophrenia is not found until later in adolescence Thompson, Paul M. et al. (2001) Proc. Natl. Acad. Sci. USA, 98, 11650 -11655

Norvegian TIPS Study (2005) • Comparing health regions in which an early psychosis detection program was introduced in two areas without such a program DUP could be substantially reduced in the experimental regions Patients entering care in the early detection regions, were in better clinical conditions and had been at less risk of suicide (Mc Gorry et al, 2007)

Norvegian TIPS Study (2005) Positive clinical differences were maintained at the 3 months follow-up and at 1 year the level of negative symptoms was significantly less; social recovery was better in the sample detected early Moreover there was a reduction of the perceived family burden (Mc Gorry et al, 2007)

Prevention of psychosis: subjects with prodromal symptoms Marshall et Rathbone, 2011

58 CONTROLLED TRIALS: (84 references, given multiple study pubblications) 17 psychosocial interventions 32 biological interventions 8 SYSTEMATIC REVIEWS and META-ANALYSES (8 references) 9 integrated interventions 2 medication withdrawn

Use of antipsychotic medication in at-risk individuals Current clinical guidelines do not recommend antipsychotics as first-line treatment for UHR individuals, as they may respond to nonpharmacological interventions and may be ‘false positives’, but antipsychotics are prescribed in this population. The second generation agents represent first-line treatment Starting treatment even before the onset of psychosis may further improve outcome New diagnosis might in fact reduce inappropriate prescription of antipsychotic medications because a patient with this diagnosis may be less likely to be prescribed antipsychotic medications than if they receive a Psychotic Disorder NOS diagnosis Nelson and Yung, 2011

AP medications are not usually indicated unless the person meets the criteria for a DSM-IV/ICD-10 psychotic disorder Exceptions should be considered with: • • rapid deteriorations suicidal risk resistant depression aggression or hostilty Clinical Guidelines: “If Antipsychotics are considered, Atypical medications should be used in low doses and considered as a ‘therapeutic trial’ for a limited period”

11 trials, 1246 participants, 8 comparisons OUTCOME: reducing transition to psychosis at 12 months CBT vs. supportive counseling (RR 0. 54) Olanzapine vs placebo (RR 0. 43) omega-3 FA (RR 0. 13 – 0. 18) Integrated psychotherapy vs supportive (RR 0. 19 – 0. 32) BUT… low quality evidence! Stafford et al. , 2013 BMJ

Although evidence of benefits for any specific intervention is not conclusive, these findings suggest that it might possible to delay or prevent transition to psychosis Stafford et al. , 2013 BMJ

When should antipsychotic therapy be introduced? The timing of introduction of antipsychotic medication should be closely linked to the onset of threshold and sustained positive symptoms of a certain level of severity and persistence However, some patients with subthreshold positive symptoms but other clinical features may need antipsychotic medications to get better, while some who cross the positive symptom threshold for psychosis and attract a DSM diagnosis within the schizophrenia spectrum may respond to simpler nonbiological interventions Defining the boundary is complex, and probably depends on both symptomatic, functional and cognitive measures Francey et al, 2010

How long should antipsychotic therapy be employed? • If there is a benefit and resolution of symptoms after 6 weeks, the medication may be continued with the patient’s consent for a further 6 months to 2 years, following explanation of risks and benefits. • After this period, a gradual attempt to withdraw the medication should be made if the patient agrees and there has been a good recovery. • If the patient has not responded to one atypical AP, another may be tried if the above indications still exist • If young people with an at-risk mental state are not seeking help, then regular contact with family members or friends may be an appropriate strategy

Antipsychotic Intervention: Pros and Cons Intervention may delay conversion to psychosis and ameliorate symptoms during the active phase of treatment but there is no evidence of lasting effects after treatment cessation Long-term use of even low doses of antipsychotic medication cause sensitization of dopamine receptors in the brain This has been suggested to possibly lead to supersensitivity psychosis or rapidonset psychosis following cessation of antipsychotic medication This suggests an additional risk not considered in previous clinical trials that incorporate cessation as part of the research design Larson et al, 2010

…HOW TO INTERVENE: POTENTIAL STRATEGIES FOR PREVENTION IN AT-RISK GROUPS • Improving suboptimal maturation of neuronal pathways • • Glutamatergic compounds GABA-ergic compounds Choline supplementation Anti-oxidants and agents that affect the immune response • Reducing environmental insults or their impact • Social skills training to prevent bullying and social exclusion • Early interventions to prevent drug abuse • Improving resilience • Cognitive remediation • Exercise training Sommer et al. , Nature PG Schizophrenia, 2016

Non Adherence A Complex Phenomenon What Happens Once the Door of the Doctor’s Office is Closed?

Ethical Issues • Unclear whether the risk/benefit profile of AP treatment means that they should be prescribed and for how long • Early detection risks: unnecessary anxiety and worry about illness risk when this is not warranted, being stigmatized • Early intervention risks: Medication exposure, and medication side effects • Stigmatization: arrangement of appropriate early treatment, lesser deterioration of psychological and interpersonal functioning, with shorter duration of DUP

Treatment guidelines for at-risk individuals Larson et al, 2010

Schizofrenia TRATTAMENTO DEL PRIMO EPISODIO

The selection of an antipsychotic medication The choice of drug should be made by the service user and healthcare professional together, considering: - the relative potential of individual antipsychotic drugs to cause EPS (including akathisia), metabolic side effects (including weight gain) and other side effects (including unpleasant subjective experiences) - the views of the carer where the service user agrees NICE, 2009 The choice of antipsychotic drug should be based on the drug’s profile in terms of adverse effects and each patient’s individual risk of developing particular associated side effects. Therefore, as far as possible, antipsychotic treatment should be specifically tailored to each patient suffering from schizophrenia WFSBP, 2012

First-episode schizophrenia Appropriate Strategies Gradual introduction of low-dose antipsychotic medication with careful explanation First line: SGA at the lower end of the standard dose range WFSBP Guidelines for Biological Treatment of Schizophrenia, 2012

First-Episode Psychosis (FEP) Cosa fare dopo Seven trials were identified, and these reported a higher rate of relapse in the dose reduction or discontinuation groups Per ora Linee guida consigliano mantenimento terapia a dosi piene per almeno un anno dopo remissione da un primo episodio e mantenimento mnel lungo termine per I pazienti che rispondono bene However…

Predictors of reduced treatment response Male sex, obstetric complications More severe hallucinations and delusionspoorer premorbid adjustment ; family history of psychosis, longer DUI and DUP; Attention deficits Parkinsonism during antipsychotics, (Robinson et al. 1999, Crespo et al. , 2013 (Oosthuizen et al. 2002) Depressive symptoms at baseline predicted fewer negative symptoms in the course and better outcome (Aguilar et al. 1994) Poor premorbid function could indicate an illness subtype less likely to respond to antipsychotic treatment regardless of when it is initiated WFSBP Guidelines for Biological Treatment of Schizophrenia

Scelte Terapeutiche Continuous treatment…intermittent treatment…placebo treatment… Intermittent or targeted treatment strategies (guided discontinuation) Alternative strategies to continuous treatment Prolonged drug holidays Extended dosing drugs do not work in patients who do not take them (Everett Koop)

Intermittent or Targeted Treatment Strategies Use of AP medication only during period of incipient relapse or symptom exacerbation, rather than continuously Prodromal symptoms are valid predictors of relapse reintroduce the treatment immediately if prodromal signs or psychotic symptoms reemerge to reduce the risk of side effects, with a further goal of improving functioning resulting from the reduction of antipsychoticinduced side effect Medication are used only when needed

Drug Holiday Antipsychotic medication is stopped or is replaced by a placebo treatment and reintroduced for fixed periods of time, repeating this process more than once during the treatment procedure Sampson S, Mansour M, Maayan N, Soares-Weiser K, Adams CE. Intermittent drug techniques for schizophrenia. Cochrane Database Syst Rev. 2013

Intermittent Treatment versus Continuous Treatment relapse three times higher for patients in the intermittent condition, compared with those in the active treatment condition

Treatment response declines with each relapse PANSS total score Second treatment course Lower symptom severity First treatment course *** *** *** * Weeks *p<0. 05; ***p<0. 001 versus second treatment course PANSS=Positive and Negative Syndrome Scale Agid et al. Neuropsychopharmacology 2014; 39: S 373–S 374; Zipursky et al. Poster at ACNP 2014

I tassi di ricaduta sono più bassi con il trattamento antipsicotico continuo Tassi di ricaduta dopo 1 anno di terapia di mantenimento, continua o intermittente, con antipsicotici convenzionali Continua Intermittente 20 Schooler et al. , 1993 32 15 Pietzcker et al. , 1993 35 7 Jolley et al. , 1989, 1990 30 10 Herz et al. , 1991 29 33 Carpenter et al. , 1990 55 0 10 20 30 40 50 60 Tasso di ricaduta (%) Kane JM. N Engl J Med 1996; 334: 34– 41

65 randomised controlled trials, data for 6493 patients primary outcome: relapse between 7 and 12 months RR = 0. 40, NNTB= 3, 95 Antipschotic drugs reduce relapse rates at 1 year (Drug 27% vs placebo 64%) Maintenaince treatment with AP benefits patients with schizophrenia Leucht et al. , Lancet, 2012

L’importanza della relazione terapeutica per gestire la complessità dei disturbi psichiatrici gravi Un modello di cura fondato sulla reciproca collaborazione nel quale il paziente sia parte attiva del trattamento e focalizzato sul potenziamento delle abilità del soggetto ad affrontare le conseguenze legate alla malattia (Berk et al. , 2004) L’approccio più corretto è quello che prevede di fornire informazioni chiare sulla malattia e i farmaci utilizzati Identificare in ciascun paziente i segni prodromici caratteristici e i sintomi che preludono la riacutizzazione di malattia È stato dimostrato che i pazienti possono riconoscere validamente i prodromi e i sintomi iniziali di una riacutizzazione della sintomatologia Riduzione della cronicità del disturbo Riduzione del rischio di ricadute (Jackson et al. , 2003)

Non-pharmacological interventions to improve physical health in FEP L’aspettativa di vita continua ad essere ridotta rispetto alla popolazione generale (malattie cardiovascolari, aumento di peso, ridotto esercizio fisico, alimentazione e fumo di sigaretta): ca. 10 anni in meno rispetto soggetti sani Le evidenze disponibili su interventi per la salute fisica (soprattutto gestione del peso e interruzione del fumo) derivano principalmente da studi su pazienti cronici. Gli interventi non-farmacologici sviluppati finora per soggetti FEP non sono al momento soddisfacenti: i risultati non perdurano oltre la fine dell’intervento. Gates et al, Lancet Psychiatry 2015

Non-pharmacological interventions to improve physical health in FEP Outcome variables • Primary outcomes • Weight, body-mass index, and waist circumference • Blood pressure • Dietary intake • Physical activity level • Tobacco use • Fasting blood glucose and lipids • Risk of cardiovascular disease • Secondary and mediating or moderating outcomes • Intrinsic and extrinsic motivation • Self-efficacy and competence to make changes to physical health behaviour • Quality of life • Relatedness • Vocation status • Positive and negative symptoms of psychosis • Symptoms of depression and anxiety Gates et al, Lancet Psychiatry 2015

Cosa intendiamo per “cura” nel caso dei disturbi psichici gravi Scomparsa permanente dei sintomi che causano sofferenza Remissione Scomparsa dei sintomi che causano sofferenza Guarigione Scomparsa permanente dei sintomi che causano sofferenza + ritorno al normale funzionamento Il concetto di Cura Ampio spettro di significato Risposta Riduzione dei sintomi che causano sofferenza

La guarigione dalla schizofrenia “Per una patologia come la schizofrenia, la guarigione completa implica la capacità di “function” nella società, sia relazionale sia professionale, oltre all'assenza di psicopatologie correlate al disturbo. La guarigione è un fenomeno più complesso e più a lungo termine rispetto alla semplice remissione. La remissione è necessaria ma non sufficiente per la guarigione” Andreasen et al. Am J Psychiatry 2005; 162: 441– 449

Remission Symptomatic Functional

Per parlare di remissione sintomatica, e’ necessario un periodo superiore ai 6 mesi di sintomi lievi o assenti su tutti gli items delle rating scales

Real World functional Illness activity variables current symptoms and remission status stability during the past three years Functional capacity assessing patients’ ability to cope with everyday tasks. The instrument assesses functional capacity in two domains: finance (counting money and paying bills) and communication (using UPSA-B) Functional milestones Current work situation , Housing situation and Social contacts (using Strauss-Carpenter Scale) Consider current symptoms (negative symptoms) and remission stability over time, together with age, duration of illness, gender, educational level, and current functional capacity, when predicting patients' future real-world functioning.

Enduring Remission : full symptom remission for at least 6 months …Predictors … v shorter DUP v shorter illness duration v better premorbid functioning v higher age at illness onset v more favorable initial response in acute treatment v better treatment adherence v fewer overall baseline symptoms v fewer negative symptoms v fewer positive symptoms to be favorable v female gender v no substance abuse v neurological soft signs v better cognitive functioning v treatment with second generation antipsychotics

Trattamento farmacologico della schizofrenia ADERENZA TERAPEUTICA I LAI: UNA POSSIBILE SOLUZIONE?

Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection. In an open-label study comparing patients treated with flexible doses of a LAI (n = 50) versus flexible doses of oral risperidone or haloperidol (n = 47), responders treated with a LAI had significantly (P < 0. 05) fewer all-cause discontinuations (26. 0% vs. 70. 2) greater reductions on the PANSS total score (− 39. 7 vs. − 25. 7), a higher remission rate (64. 0% vs. 40. 4%) and a lower relapse rate (9. 3% vs. 42. 1%) Emsley et al, 2008

Impact on Intracortical Myelination Trajectory of Long Acting Injection Versus Oral Risperidone in First. Episode Schizophrenia Residual z-score of frontal lobe intracortical myelin inpatients with FEP randomized to treatment with risperidone LAI vs oral Individual residual z-scores (based on healthy controls) of frontal lobe intracortical myelin (ICM) in first-episode schizophrenia subjects randomized to treatment with risperidone long-acting injection (RLAI) versus oral risperidone (Ris. O) The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. Bartzokis et al, 2012

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How is possible to switch from oral to LAI antipsychotics 4– 6 weeks 4– 12 weeks An oral conversion phase Cross-titrated to oral aripiprazole Oral stabilization phase Aripiprazole 10– 30 mg/day 12– 36 weeks AOM 400 stabilization phase Concomitant oral aripiprazole for the first 2 weeks at flexible doses of 10– 30 mg/day Peters-Strickland et al. npj Schizophrenia (2015) 1– 4 weeks Phase A: An oral conversion phase Cross-titrated to 10– 30 mg oral aripiprazole The starting dose was 10 or 15 mg/day 4– 12 weeks Phase B: AOM 400 mg once monthly Aripiprazole 10– 30 mg/day For the first 14 days, concomitant oral (10– 20 mg) aripiprazole was administered Kane et al. J Med Econ. 2015

Rationale of switching from oral to LAI aripirazole Oral aripiprazole administration (10– 30 mg/day) Intramuscolar (400 -300 mg/day) aripiprazole administration Concomitant oral aripiprazole for the first 2 weeks at flexible doses of 10– 30 mg/day Peters-Strickland et al. npj Schizophrenia (2015); Kane et al. J Med Econ. 2015

Problemi e limiti della Psichiatria Nella psichiatria, al medico si presenta un mondo estraneo a tutte le altre discipline… è necessaria una preparazione completamente diversa. Ne consegue che la psichiatria, essendo praticata da medici che non posseggono una preparazione specifica nelle scienze dello spirito, non ha, come scienza, uno sviluppo uniforme, e così il giovane medico fa i suoi studi psichiatrici più o meno a caso e molti psichiatri sono scientificamente dei dilettanti… K. Jaspers, 1964