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Firenze, 11 aprile 2014
Disturbo Bipolare e
Demenza:
una Relazione Complessa
Claudio Vampini
Dipartimento per la Salute Mentale
e Università di Verona
Disturbo Bipolare e Demenza:
una Relazione Complessa
Disturbo Bipolare
Litio / Valproato?
Demenza
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Prevalence of Dementia in Europe
Pooled analyses of 11 studies from the EURODEM group (Lobo et al., 2000)
\
Ott A, et al. Incidence and risk of dementia. The Rotterdam Study. Am J Epidemiol 1998; 147(6): 574-580
Hebert R, Brayne C. Epidemiology of vascular dementia. Neuroepidemiology 1995; 14: 240-257
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Prevalence of Bipolar Disorder in Older
Adults in Various Setting
Setting
N° of Studies
Prevalence
(Gen Pop: 0.5 – 6%)
Community studies
4
0.08% - 0.46%
Inpatients psychiatry
11
8 - 10 %
Outpatients
psychiatry
Long-term care
istitutions
Psychiatric emergency
rooms
3
2 - 8%
3
3 - 17.4%
2
14 - 17%
Depp & Jeste, Bipolar Disord 2004; 6(5): 343–67
Sajatovic et Al, Am J Geriatr Psychiatry 2005;13:282-289
Depression (D)
Early-onset D: 2X Dementia Risk
Late-onset D: most studies support
an association
(> severity, male g, education)
Dementia
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Disturbo Bipolare e Demenza:
una Relazione Complessa
Disturbo Bipolare
Early-onset
Late-onset
Demenza
Disturbo Bipolare e Demenza:
una Relazione Complessa
Disturbo Bipolare
Early-onset
Demenza
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Deficit Cognitivo nel Disturbo Bipolare
• Presente già in fase premorbosa e poi in eutimia.
• Apprendimento, memoria verbale, funzione
•
•
•
esecutiva.
Peggiora nel follow-up (>> funzione esecutiva)
Predittori di gravità:
n° episodi di malattia
n° episodi maniacali
sintomi depressivi residui
durata di malattia
Stile di vita, malattie fisiche/SNC, terapie?
Robinson & Ferrier. Bipol Dis, 2006;8:103-116; Torrent et al, J Clin Psych, 2012;73 e899-e905
•Does
Rate the
of dementia
increased 13%
with every
episode
forthe
risk of developing
dementia
increase
with
patients
with Depressive
and 6% with
Bipolar
n° of episodes
in patientsDisorder
with Depressive
Disorder
and in
patients with
Bipolar
Disorder
? (1970 -1999)
Disorder,
when
adjusted
for differences
in age and sex.
HR disturbo depressivo; n 18726
HR disturbo bipolare; n 4248
IC 95%
1 episodio*
2 episodi
3 episodi
4 episodi
Tipo
≥5 episodi di disturbo§
*Tasso di diagnosi di demenza per i pazienti con un certo numero di episodi rispetto al
tasso per i pazienti con un episodio precedente. §L’effetto del tipo di disturbo per i pazienti
con un episodio
Kessing et al. Neurol Neurosurg Psychiatry 2004;75:1662-1666
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3.2
• N: 13 DB, 70.8 (± 7.7) a.
• Demenza dopo 29.1 (± 10.1) a. da esordio di DB.
MMSE medio 24.0 (± 4.3)
• Follow-up 6.1 a. (± 2.8)
MMSE medio: 23.5 (± 3.2)
modesta sindrome comportamentale frontale
SPECT: ipocaptazione FT (PAR) bilaterale
non soddisfatti criteri per AD, VaD, FTD, LBD
• Possibile “Demenza post-DB” ?
BvFTD and Primary Mania: Overlap in Symptoms
• Euphoria: inappropriate childlike jocularity (e.g. repetitive
phrases and jokes), vs. pressured speech and sustained
emotional intensity.
• Disinhibition: undue familiarity, carelessly voicing
insulting observations, petty theft, sexual acting out, or
poor financial decisions.
• Complex stereotyped movements, vocalizations, and other
compulsions may resemble agitation seen in BD.
• Mindless habits are invariant, vs. variable, impulsive
expressions of intense emotion, as seen in true mania.
• BvFTD vs. BD: insidious onset and progressive nature,
stereotyped movement and speech, disinhibition without
remorse, profound loss of empathy and social sensitivity,
overeating or compulsive eating, lack of insight and
concern, absence of periodicity.
Woolley et Al, J Clin Psychiatry. 2011 February ; 72(2): 126–133.
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Disturbo Bipolare e Demenza:
una Relazione Complessa
Disturbo Bipolare
Late-onset
Demenza
Late-onset Bipolar Disorder: a Distinct Subtype?
Age at first admission in patients with and without family
psychiatric history.
30
n=277
Number of cases (%)
p: 0.029
Familial by set criteria
Non-familial
20
10
p: 0.007
“Mixed Features”
0
12 17 22
27 32 37 42 47 52 57
62 72 77
82 87
Age of first admission (years)
All patients discharged from a district in-patient service diagnosed with Bipolar Disorder in a 7-year
period were ascertained from a case register
Moorhead SRJ, Young AH. J Affect Disord 2003;73:271-277
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Mixed States and “Pseudodementia”
Mood disorder: from the sixth to seventh decade
of life and onward.
Attention and concentration problems.
MIXED features: mood instability, irritability,
agitation, irregular drive and sleep.
“Strong” temperament, extremely active life
earlier, often with a charismatic style, but more
manifest in strong sexual indiscretions in recent
months.
Possible evolution in dementia.
Akiskal et al, 2011; Perugi, SOPSI, 2014, mod
“Vascular
Mania”
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Iperintensità della sostanza bianca nei gangli della
base e in regione frontale e parietale in p.ti anziani
con DB ad esordio precoce e tardivo (>60 a.)
#
#
L.O.
*p=0,018; +p=0,027; §p=0,006; ^p=0,045
#PV-WMH=iperintensità della sostanza bianca periventricolare
##D-WMH=iperintensità della sostanza bianca profondaa
##
E.O.
Tamashiro et al. Bipolar Disorders 2008:10:765-775
• Later age of first manic episode and greater
vascular disease burden were related to lower
memory performance.
• There is arguably a BD “vascular subtype”, where
vascular brain changes are related to mania and
cognitive decrements in late life.
Gildengers et al, 2010
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Proposed predominant pathways linking Depression
(Bipolar Disorder?) to the onset of Dementia
Bipolar Disorder
The pathways linking depression and dementia are likely to be multifactorial and
probably not sequential.
Byers, A. L. & Yaffe, K. Nat. Rev. Neurol. 7, 323–331 (2011)
Disturbo Bipolare e Demenza:
una Relazione Complessa
Disturbo Bipolare
Demenza
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Bipolar Type VI ?: "Bipolarity" in the Setting of
Dementia
• Demenza conclamata, senza storia di DB
• «Mixed Features» BPSD: instabilità umorale,
disforia, agitazione, ansia, irritabilità,
CNS Spectr. 2008;13(9):796-803
disinibizione, aggressività
• Temperamento ipertimico, ciclotimico, irritabile
• Familiarità per DB formale o spettro bipolare
• Peggio con AD; meglio con basse dosi di SU o SGA
Disturbo Bipolare e Demenza:
una Relazione Complessa
Disturbo Bipolare
Litio / Valproato?
Demenza
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Litio negli Anziani con Mania Acuta
• Nessun RCT
• Dosi ridotte del 25-50% vs. adulti giovani
• Range terapeutico consigliato: 0.5 - 0.8 mEq/L
65 – 75 anni: 300 - 600 mg/d
≥ 80 anni: 150 - 300 (450) mg/d
• Elevata variabilità interindividuale
• Possibili litiemie elevate a basso dosaggio
per modificazioni e/o interazioni cinetiche
• Valutare età, tollerabilità, fragilità
Sproule et al, Drugs & Aging, 2000, 16, 3, 165-177
Aziz et al, Am J Geriatr Pharmacotherapy, 2006, 4, 347-364
Young et al. Am J Ger Psychiatry 2004;12:342-357
Brain Lithium Levels and Effects on Cognition and Mood
in Geriatric Bipolar Disorder: A Lithium - 7 Magnetic
Resonance Spectroscopy Study
• Brain Li levels do not
correlated with serum
Li for subjects ≥ 50 yo
•• The
absence
a
Elevations
in of
brain
predictable
(but not serum) Li
relationship
between
levels were associated
serum
and brain
with frontal
lobe Li
makes
specific
dysfunction and
individual
predictions
higher HDRS
scores
about the “ideal” Li
serum level in an older
adult with BD difficult.
N 26
(50 - 85 years old: N 10)
•
Li crosses the BBB with a mean ratio of serum
to CSF Li of 3.6 : 1
Forester et Al, Am J Geriatr Psychiatry 2009; 17:13–23
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Litio: Neurotossicità negli Anziani
•
•
•
•
Confusione, atassia, acatisia, delirium
Anche con litiemia in range per possibile
incremento del Li intracellulare*
Più frequente nelle manie "secondarie”
Favorita da:
sofferenza SNC clinica o subclinica
associazione con AP (FGA > SGA)
SMN
associazione con SSRI/SNRI
Sindrome
Serotoninergica
Young et al, 2004; Sajatovic et al, 2005; Aziz et al, 2006; *Forester et al, 2009
Valproato negli Anziani con Mania Acuta
• Dosaggi: 125 >> 250 - 2.250 mg/die
• Efficacia indipendente dal livello
plasmatico
• Mania late-onset
• Mania secondaria a:
patologie mediche
patologie neurologiche
–
1 RCT nella mania in corso di demenza
Young et al. 2004, Am J Ger Psychiatry 12,342-357;Tariot et al, 2001, Curr Ther Res, 62, 51-67
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Valproato: Neurotossicità negli Anziani
•
•
•
•
Tremore fine
Sedazione
Atassia, parkinsonismo
Delirium
↑ Rapido dosi ?
non iperammoniemico ↑ Frazione libera ?
iperammoniemico
•
M Alzheimer: studio a 1 anno a gruppi paralleli
vs. placebo
> atrofia cerebrale (RMN) con accelerato
decadimento cognitivo?
Young et al, 2004; Sajatovic et al, 2005; Aziz et al, 2006; *Fleisher et al, Neurology, 2011;77:1263–1271
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Fountoulakis et al, International Journal of Neuropsychopharmacology (2008), 11, 269–287
Litio e Valproato: Neuroprotezione ?
potenziale apoptosi
Destabilizzazione e degradazione della β - catenina
P
+
+
+
β - catenina
+
GSK - 3 β
P
P
Tau
+
-
P
-
Li- VPA
+
PEBP2 β
+
Bcl2
“grovigli”
neurofibrillari
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• The classification of the data suggests that the evidence
is of level C, that is ‘unclear or conflicting’.
Does Lithium Protect Against Dementia?
Authors
Study
Results
Brinkman et al, 1984
Open – 5 weeks
N 14 SDAT
Li+ with mean serum concentrations up to 0.6
meq/liter did not alter memory scores significantly.
Hampel et al, 2009
Single blind –
10 weeks
N 71 SDAT
Li+ did not lead to change in the ADAS-Cog
subscale or in depressive symptoms
No effect on GSK-3 activity or CSF-based
biomarker concentrations.
Terao et al, 2006
Retrospective
N 1423 BD
Those who had previously received Li+ and/or were
currently prescribed Li+ had significantly better
MMSE scores than the control patients.
Nunes et al, 2007
Cross-sectional
N 118 older BD
Kessing et al, 2010
Retrospective
N 4856 BD
Forlenza et al, 2011
RCT – 12 months
N 45 MCI
Li+ treatment reduced the prevalence of AD in
patients with BD to levels in the general elderly
population.
Continued treatment with Li+ was associated with a
reduced rate of dementia in patients with BD.
Li+ treatment was associated with a significant
decrease in CSF concentrations of P-Tau and
better performance on the cognitive subscale of
the AD Assessment Scale and in attention tasks.
C. Vampini, F. Nifosì, NOOS, VOL 19 N 3, 2013
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Conclusioni
•
Il Disturbo Bipolare è associato, nel follow-up, ad
incremento della diagnosi di demenza.
•
La diagnosi differenziale è più complessa per DFT
che per AD o VaD.
• Fattori patogenetici comuni o associazione casuale?
• Late-onset «vascular mania»: quale rischio di
evoluzione in VaD?
•
DB tipo VI con «mixed features»: slatentizzazione
di diatesi bipolare in corso di AD?
•
•
Litio e valproato: neurotossici, neuroprotettivi ?
Future ricerche: batterie di test, brain imaging,
biomarkers di AD nella fase precoce del DB.
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