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Disturbo Bipolare e Demenza:

una Relazione Complessa

Firenze, 11 aprile 2014

Claudio VampiniDipartimento per la Salute Mentale

e Università di Verona

Disturbo Bipolare

Disturbo Bipolare e Demenza: una Relazione Complessa

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): 574-580Hebert R, Brayne C. Epidemiology of vascular dementia. Neuroepidemiology 1995; 14: 240-257

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Setting N° of Studies Prevalence(Gen Pop: 0.5 – 6%)

Community studies 4 0.08% - 0.46%

Inpatients psychiatry 11 8 - 10 %

Outpatientspsychiatry

3 2 - 8%

Long-term care istitutions

3 3 - 17.4%

Psychiatric emergencyrooms

2 14 - 17%

Depp & Jeste, Bipolar Disord 2004; 6(5): 343–67

Sajatovic et Al, Am J Geriatr Psychiatry 2005;13:282-289

Prevalence of Bipolar Disorder in OlderAdults in Various Setting

Depression (D)

Dementia

Early-onset D: 2X Dementia Risk

Late-onset D: most studies support

an association

(> severity, male g, education)

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Disturbo Bipolare

Demenza

Late-onset

Early-onset

Disturbo Bipolare e Demenza: una Relazione Complessa

Disturbo Bipolare

Demenza

Disturbo Bipolare e Demenza: una Relazione Complessa

Early-onset

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• 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

Deficit Cognitivo nel Disturbo Bipolare

HR disturbo bipolare; n 4248 HR disturbo depressivo; n 18726

IC 95%

1 episodio * 2 episodi 3 episodi 4 episodi ≥5 episodiTipo

di disturbo §

Does the risk of developing dementia increase with the

n° of episodes in patients with Depressive Disorder and in

patients with Bipolar Disorder ? (1970 -1999)

• Rate of dementia increased 13% with every episode for

patients with Depressive Disorder and 6% with Bipolar

Disorder, when adjusted for differences in age and sex.

*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” ?

• Euphoria : inappropriate childlike jocularity (e.g. repetitive phrases and jokes), vs. pressured speech and sustai ned 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 man ia.

• BvFTD vs. BD : insidious onset and progressive nature, stereotyped movement and speech, disinhibition with out remorse, profound loss of empathy and social sensit ivity, overeating or compulsive eating, lack of insight an d concern , absence of periodicity.

BvFTD and Primary Mania: Overlap in Symptoms

Woolley et Al, J Clin Psychiatry. 2011 February ; 72(2): 126–133.

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Disturbo Bipolare

Demenza

Late-onset

Disturbo Bipolare e Demenza: una Relazione Complessa

Late-onset Bipolar Disorder: a Distinct Subtype?Age at first admission in patients with and without family psychiatric history.

Moorhead SRJ, Young AH. J Affect Disord 2003;73:271-277

30

17 22 27 32 37 42 47 52 57 62 72 77 82 87120

10

20

Age of first admission (years)

Num

ber

of c

ases

(%)

Familial by set criteriaNon-familial

All patients discharged from a district in-patient service diagnosed with Bipolar Disorder in a 7-year

period were ascertained from a case register

n=277

p: 0.029

p: 0.007

“Mixed Features”

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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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Tamashiro et al. Bipolar Disorders 2008:10:765-775

####

*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

L.O. E.O.

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.)

Gildengers et al, 2010

• 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.

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Proposed predominant pathways linking Depression (Bipolar Disorder?) to the onset of Dementia

The pathways linking depression and dementia are li kely to be multifactorial and probably not sequential. Byers, A. L. & Yaffe, K. Nat. Rev. Neurol. 7, 323–331 (2011)

Bipolar Disorder

Disturbo Bipolare

Demenza

Disturbo Bipolare e Demenza: una Relazione Complessa

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CNS Spectr. 2008;13(9):796-803

Bipolar Type VI ?: "Bipolarity" in the Setting of

Dementia

• Demenza conclamata, senza storia di DB

• «Mixed Features» BPSD: instabilità umorale,

disforia, agitazione, ansia, irritabilità,

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

Disturbo Bipolare e Demenza: una Relazione Complessa

Demenza

Litio / Valproato?

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• 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, 165-177Aziz et al, Am J Geriatr Pharmacotherapy, 2006, 4, 347-364

Young et al. Am J Ger Psychiatry 2004;12:342-357

Litio negli Anziani con Mania Acuta

Brain Lithium Levels and Effects on Cognition and Mood in Geriatric Bipolar Disorder: A Lithium - 7 MagneticResonance Spectroscopy Study

Forester et Al, Am J Geriatr Psychiatry 2009; 17:13–23

N 26 (50 - 85 years old: N 10)

• Brain Li levels do not correlated with serum Li for subjects ≥ 50 yo

• Li crosses the BBB with a mean ratio of serum to CSF Li of 3.6 : 1

• Elevations in brain (but not serum) Li levels were associated with frontal lobe dysfunction and higher HDRS scores

• The absence of a predictable relationship between serum and brain Li makes specific individual predictions about the “ideal” Li serum level in an older adult with BD difficult.

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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)

�associazione con SSRI/SNRI

SMN

Young et al, 2004; Sajatovic et al, 2005; Aziz et al, 2006; *Forester et al, 2009

Sindrome Serotoninergica

Valproato negli Anziani con Mania Acuta

Young et al. 2004, Am J Ger Psychiatry 12,342-357;Tariot et al, 2001, Curr Ther Res, 62, 51-67

• 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

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• Tremore fine

• Sedazione

• Atassia, parkinsonismo

• Delirium

� iperammoniemico

� non iperammoniemico

• M Alzheimer: studio a 1 anno a gruppi paralleli vs. placebo

� > atrofia cerebrale (RMN) con accelerato decadimento cognitivo?

Valproato: Neurotossicità negli Anziani

↑↑↑↑ Rapido dosi ?↑↑↑↑ Frazione libera ?

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

“grovigli” neurofibrillari

PTau +

ββββ - catenina

P

P

GSK - 3 ββββP

Destabilizzazione e degradazione della ββββ - catenina

potenziale apoptosi

PEBP2 ββββ Bcl 2-++

+

+

+

+

-

-

-

Li- VPA

Litio e Valproato: Neuroprotezione ?

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• The classification of the data suggests that the ev idence 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

Li+ treatment reduced the prevalence of AD in

patients with BD to levels in the general elderly

population.

Kessing et al, 2010 Retrospective

N 4856 BD

Continued treatment with Li+ was associated with a

reduced rate of dementia in patients with BD.

Forlenza et al, 2011 RCT – 12 months

N 45 MCI

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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• 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.

Conclusioni