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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
“First Episode” Schizophrenia:
Duration of
untreated psycoses
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

Melbourne Criteria

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

Based on these criteria, the rate of transition to
psychosis is 41% within a one-year follow-up period

Ultra high risk criteria
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
SINTOMI PSICOTICI
LIVELLO FENOMENICO
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:
 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
 Continuum fenomenologico di Erlebnisse intermedi
progressivamente più caratteristici, che connette i Sintomi di
Base ai sintomi diagnostici della schizofrenia
 non destrutturazione della personalità, ma una personalità
limitata nelle sue potenzialità e nella sua efficienza
 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 C1.17 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»
• 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

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)
Marshall et Rathbone, 2011
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
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
“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?
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 can 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
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
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
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
(Aguilar et al. 1994)
(Oosthuizen et al. 2002)
Depressive symptoms at
baseline predicted fewer
negative symptoms in the
course and better outcome
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…
Alternative strategies to
continuous treatment
Intermittent or
targeted
treatment
strategies (guided
discontinuation)
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:S373–S374; 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
Guarigione
Scomparsa
permanente dei
sintomi che
causano sofferenza
Remissione
Scomparsa
permanente dei
sintomi che causano
sofferenza + ritorno al
normale
funzionamento
Il concetto di Cura

Ampio spettro di
significato
Risposta
Scomparsa dei
sintomi che
causano sofferenza
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 …
 shorter DUP
 shorter illness duration
 better premorbid functioning
 higher age at illness onset
 more favorable initial response in acute treatment
 better treatment adherence
 fewer overall baseline symptoms
 fewer negative symptoms
 fewer positive symptoms to be favorable
 female gender
 no substance abuse
 neurological soft signs
 better cognitive functioning
 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 FirstEpisode 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 (RisO)
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
1
2
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