Depressione e Demenza

Leo Nahon - Francesca Malchiodi S.C. Psichiatria 3 Az Osp

Niguarda.Milano 58 Congresso SIGG-Torino 29.11.13

The Doctors’Dilemma ?

• Al di la delle evidenze neurobiologiche (dall’imaging ai tests neuropsicologici) degli RCT e della ricerca epidemiologica, mai come nel caso del rapporto tra Depressione e Demenza il clinico dev’essere addestrato a sentire con la propria capacità di presenza di fronte al malato , coi propri sensori soggettivi della malattia, il dilemma depressione/demenza come lo può sentire il soggetto interessato.

Nahon/Malchiodi

“Medico usa te stesso..!”

• Esiste una zona cieca infatti, una fascia di non rilevabilità, una zona non bene illuminata da EBM che sta tra la sintomatologia depressiva e quella della incipiente decostruzione dementigena che nessuno strumento se non il sentire clinico può intuire . O che comunque meglio può rilevare di altri markers più obbiettivi.

Nahon/Malchiodi

Nahon/Malchiodi

The Patient’s Dilemma

• Dilemma che se per noi operatori è diagnostico e in buona misura anche prognostico, per il/la nostro/a paziente è un dilemma vissuto minuto per minuto nello sfaldamento della propria esistenza con una forte marcatura di incomprensibilità, smarrimento, estraneità, di lancinante e nebbiosa sensazione che la vita stessa della mente se ne stia andando.

Nahon/Malchiodi

Il velo dell’Apatia/Lo strappo dell’Irrequietezza

• Sono spesso situazioni immerse nel rallentamento, nella perdita di iniziativa nell’ affievolimento della volontà , fino alla rassegnazione, l’ indifferenza e l’apatia.

• Alternate spesso a uno stato d’inquietudine, insofferenza, scatti d’irascibilità e improvvise crisi di pianto e di pentimento furente.

• Il velo della tristezza avvolge la rabbia e l’impulsività.

Nahon/Malchiodi

Factor analysis revealed five distinct neuropsychiatric syndromes:

• the apathetic syndrome (as unique syndrome) was the most frequent,

• affective syndrome (anxiety and depression),

• psychomotor (agitation, irritability, and aberrant motor behavior),

• psychotic (delusions and hallucinations),

• and manic (disinhibition and euphoria).

More than three quarters of patients with AD presented with one or more of the syndromes (N = 790, 77.8%), and more than half exhibited clinically significant severity of symptoms (N = 603, 59.4%).

NEUROPSYCHIATRIC SYMPTOMS AND SYNDROMES IN A LARGE COHORT OF NEWLY DIAGNOSED, UNTREATED PATIENTS WITH

ALZHEIMER DISEASE.

Spalletta,..Canonico, et al. The American journal of Geriatric Psychiatry, 2010

“ Non so perché ma l’ho fatto..”

Ma questo velo viene lacerato a volte da uno spaventoso tuffo nella dimensione della morte : un “esordio” suicidale quasi sempre inaspettato che costituisce l’incipit della Depressione demente o della Demenza depressiva dell’Anziano. E che in realtà rappresenta un paradossale aumento dell’insighit insieme a un prevalere degli elementi impulsivi non più imbrigliati dalla cognitività. Nahon/Malchiodi

Monicelli ,Lizzani, Magri, e i tanti altri ..

• Il suicidio a “sorpresa” va considerato tendenzialmente come una sottovalutazione di pregresse patologie psichiatriche, ma anche una grande difficoltà nel tollerare il dolore mentale ; perché tanti altri invece

capiscono che la morte arriva e in qualche modo si addestrano ad accoglierla…

• (Alce nero parla…)

Imaging negativo..Test ai limiti..

• E non solo il sentire del medico va attivato ma, insieme il sentire dei familiari del paziente, del suo gruppo di pari, dei suoi vicini, del suo gruppo sociale, dei caregivers - se già ci sono, va chiamato in proscenio per prevenire questo tipo di esordio; e ogni strumento dell’orchestra deve far sentire la sua intonazione e il suo tema principale.

Quando, naturalmente, ciò sia possibile.

Nahon/Malchiodi

Nahon/Malchiodi

le sei ipotesi

• It is true that depression often follows dementia, but there is also the possibility that it enhances a person’s vulnerability to dementia. Jorm reviewed the literature and found six hypotheses that may explain the association between depression and dementia:

• (i) depression treatments are a risk factor for dementia; • (ii) dementia and depression share common risk factors; • (iii) depression is a prodrome of dementia; • (iv) depression is an early reaction to cognitive decline; • (v) depression affects the threshold for manifesting

dementia • (vi) depression is a causal factor in dementia.

Nahon/Malchiodi

Shiraishi

• Jorm conducted a meta-analysis and found that depression was associated with an increased risk of subsequent dementia in both case control and prospective studies (95% confidence intervals for relative risk 1.16–3.50 and 1.08–3.20, respectively). He concluded that there is sufficient evidence to take seriously the possibility that depression is a risk factor for dementia and cognitive decline. There have been other reports that support the notion that depression heightens the risk of dementia

Nahon/Malchiodi

Nahon/Malchiodi

• The last two decades have witnessed significant advances in our understanding of the neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical functioning are implicated.

• New biomedical models extend well beyond perturbations of traditional monoamine systems to include altered neurotrophins, endocrinologic and immunologic system dysfunction, inflammatory processes and gene expression alterations. This more recent research has highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute to the various phenotypic presentations.

Nahon/Malchiodi

The mechanism by which depression itself may cause

memory decline remains to be determined but there is

evidence suggesting that the down-regulation of the HPA

axis may be relevant, as well as the associated neurotoxic

effects of gluco- corticoids, and reduced expression of

brain-derived neurotrophic.

There is emerging evidence linking poorer memory

performance and hippocampal functioning in

depression

Nahon/Malchiodi

When evaluating memory functioning in Late Life Depression, it is

important to consider which aspects of memory processing are impaired.

That is, insights regarding underlying pathophysiological changes can be

gleaned by determining whether difficulties are apparent in memory

‘encoding’, ‘storage’ or ‘retrieval’.

The differentiation of these various aspects of memory is relevant since they

likely reflect dysfunction within distinct neurobiological circuitry, with the

former reflecting dysfunction within prefrontal or frontotemporal circuits and

the latter being reflective of mesial temporal lobe dysfunction including

hippocampal compromise.

Nahon/Malchiodi

Similia cum Similibus

• Caratteristiche comuni in Demenza in esordio e Depressione “cognitiva”

- alterazione dell’attenzione e della memoria di lavoro

- modificazione del ritmo sonno-veglia

- riduzione delle abilità sociali e del funzionamento occupazionale

Nahon/Malchiodi

Nahon/Malchiodi

Fattori comuni: Wuwongse et al./ Progress in Neurobiology 91 (2010)

M. di Alzheimer:

-segni patologici (Aβ

placche; tau

iperfosforilate) - processi

neurodegenerative

(apoptosi, autofagia,

disfunzione

mitocondriale, stress ossidativo, alterazione

del trasporto assonale)

Depressione Maggiore:

-Deficit monoamine

-Alterazioni dell’asse HPA

Neuroinfiammazione:

citochine pro-

infiammat

citochine anti-infiammat

fattori neurotrofici

degenerazione sinaptica

Nahon/Malchiodi

Dementia is associated with increased risk of

developing depression, and conversely depression seems to increase the risk

of subsequently developing dementia.

is depression simply a prodromal initial state of dementia or an

independent risk factor for dementia years before the onset of

dementia? Nahon/Malchiodi

Depressione: fattore di rischio e/o prodromo della demenza?: Entrambi !

1)La Depressione Maggiore si evidenzia spesso nei pazienti affetti da demenza (20% in Alzh; 50% in Dem Vascolare):

2) la Depressione può essere una reazione ai deficit cognitivi iniziali (aumento dell’insight prima della sua perdita ?)

3) la Depressione altera le funzioni cognitive

Nahon/Malchiodi

Nahon/Malchiodi

• “Evidenze convergenti suggeriscono che sintomi o sindromi depressive ad esordio tardivo spesso siano prodromi di un declino cognitivo. Una storia recente di depressione è associata con un’aumentata incidenza di AD.

• Gli individui con una depressione a esordio tardivo e alterazione cognitiva transitoria frequentemente sviluppano un AD o un VaD entro pochi anni dalla Depressione

Nahon/Malchiodi

La Depressione è un fattore di rischio per la demenza vascolare

• La Depressione può rappresentare un fattore di rischio indipendente, predisponente ai Dementing Disorders anche quando i sintomi depressivi compaiano più di 10 anni prima dell’esordio della demenza.

• Una storia di Depressione lifetime aumenta il rischio di AD a prescindere dalla familiarità per i Dementing Disorders . (Panza et al 2010)

Nahon/Malchiodi

• Moreover, the findings reviewed suggested

that in primary MDD, the task is to figure out

if the cognitive impairment is reversible or

progressive in nature.

• In primary MCI, the task may be to figure

out if depressive symptoms or a particular

depressive pattern may predict progression

to dementia. (Panza et al 2010)

Nahon/Malchiodi

In patients with depression associated with dementia,

antidepressants are associated with a substantial risk

for adverse effects, and their efficacy is not proven.

In particular, studies with sertraline and mirtazapine

have yielded negative results. In our opinion, risks and

benefits of antidepressants should be carefully

evaluated when these drugs are prescribed to patients

with depression in association with dementia, and their

use should be restricted to patients with moderate and

severe depression.

Nahon/Malchiodi

• Strong supporting evidence for the notion that vascular dis- ease contributes to late-life depression comes from struc- tural MRI studies showing a robust association between ischemic brain lesions and depression diagnosis or self- reported symptoms in older persons. Large community- based studies have demonstrated independent cross-sectional relationships between late-life depression and small basal ganglia lesions and white matter abnormalities visu- alized as hyperintense regions on T2-weighted MRI (WMHs) in deep or subcortical areas. Longitudinal stud- ies suggest white matter changes may both predate and independently predict late-life depression. (2008)

Nahon/Malchiodi

Large community-based studies have demonstrated independent cross-sectional relationships between late-life depression and small basal ganglia lesions and white matter abnormalities visualized as hyperintense regions on T2-weighted MRI (WMHs) in deep or subcortical area. Longitudinal studies suggest white matter changes may both predate and independently predict late-life depression.

Nahon/Malchiodi

Brain reserve capacity: those with greater neuronal redundancy are able to tolerate more cell loss than those with less redundancy, before manifesting clinical symptoms. Brain reserve capacity posits that individual differences in neural redundancy translate into differences in thresholds for vulnerability to or protection from clinical symptoms after brain damage.

Cognitive reserve developed is similar but rather than being based on differences in brain size or neuronal count, emphasizes differences in the efficiency or manner in which tasks are per- formed or information is processed.

Nahon/Malchiodi

Brain and cognitive reserve: the final common pathway linking depression to dementia (Butter 2008)

• We propose that the reserve threshold theory is the key explanatory mechanism behind the late-life depression/dementia association. That is, through a number of processes, depression injures neurons, thus lowering reserve such that cognitive impairment is expressed earlier and/or more frequently than it would otherwise.

• As depicted in Figure 1, depression is linked to vascular disease, especially in the frontostriatal area. Depression also is linked to elevated glucocorticoid production, as well as amyloid deposition and neurofibrillary formation, each of which may lead to hippocampal injury. Each of these processes adds to the total brain injury burden, lowering reserve and vulnerability to express cognitive impairment.

Nahon/Malchiodi

Both brain reserve and cognitive reserve explain the

role of risk and protective factors for cognitive

impairment (including progressive decline into

dementia), associated with brain damage.

For example, higher educational attainment, larger

head size, larger brain volume, social engagement,

physical activity and leisure cognitive activity may

result in greater redundancy and/or efficiency and

therefore reserve, thereby offering protection against

exhibiting clinical symptoms of dementia. Nahon/Malchiodi

The link between these two conditions is not completely clarified. Depression could serves as an independent risk factor for developing AD possibly by reducing the brains ‘reserve

capacity’ and increasing neurofibrillary tangles and amyloid plaques in the

hippocampus

Nahon/Malchiodi

Rozzini,Trabucchi, e al

We found that continued long-term treatment with older

antidepressants, such as TCAs, was associated with a

reduced rate of dementia in a large population of all

patients treated in psychiatric hospital service in Denmark

during a 10-year period, whereas continued treatment

with other kinds of antidepressants was not

associated with a decreased rate of dementia. The finding

of a reduced rate of dementia that was related to

continued use of older antidepressants was replicated

with Alzheimer’s disease as the outcome but not with

dementia of other kinds.

International Clinical Psychopharmacology, 2011 Nahon/Malchiodi

Neurocognitive Costs and Benefits of

Psychotropic Medications in Older

Adults

Brooks J.O. & Hoblyn J.C., j of Geristric Psychiatry and Neurology (2007)

• Nei soggetti anziani, il declino cognitivo associato

alla depressione può essere esacerbato dal trattamento antidepressivo, che può aggravare i

deficit del funzionamento • Alcuni antidepressivi migliorano il funzionamento

neurocognitivo, indipendentemente dalla risposta antidepressiva

Nahon/Malchiodi

• Start slow & go slow…

• Attenzione all’uso di BDZs (effetti paradossi; peggioramento delle funzioni cognitive)

• Attenzione all’uso di Olanzapina o Risperidone per rischio incidenti cerebrovascolari (marcia indietro aifa?)

“Very often these old persons do not look for care

as consequence of the prevailing double stigma

attached to mental disorders in general and to the

end of life in particular”

(De Mendonça Lima, Arch. Gerontol. Geriatri. Suppl. 9, 2004: 109 -120)

STOP EXCLUSION, DARE TO CARE (1)

1 = World Health Day 2001 & World Health Report 2001 Nahon/Malchiodi

L’OSPEDALIZZAZIONE, A MAGGIOR RAGIONE SE PROLUNGATA, HA DEGLI EFFETTI COLLATERALI?

“…frequently when patients came out of hospital

the acute problem is resolved, but their functional

status was dramatically worse”

George J. et al. (2011). Age and Aging.

40: 543-548

Nahon/Malchiodi

• During the last years, a large body of evidence has been accumulated to support the use of antidementia medication in patients with severe Alzheimer’s disease.

• Combination therapy with acetylcholinesterase inhibitors and memantine for Alzheimer’s disease remains controversial, as controlled trials have yielded conflicting results.

• Memantine is not indicated in patients with mild Alzheimer’s disease. Studies on memantine for Parkinson’s disease dementia and dementia with Lewy bodies were inconclusive.

• In adult patients with dementia in the context of Down syndrome, memantine is not effective, and further studies on acetylcholinesterase inhibitors are warranted.

• There is still no treatment established for patients with vascularor frontotemporal dementia.

• The efficacy of antidepressants to treat depression associated with dementia is not proven. Treatment of agitation and psychosis in patients with dementia remains a challenge.

Nahon/Malchiodi

Nahon/Malchiodi

Conclusions: Nonpharmacological

interventions

delivered by family caregivers

have the potential to reduce the frequency

and severity of behavioral and psychological symptoms of dementia, with effect

sizes at least equaling those of

pharmacotherapy,

as well as to reduce caregivers’

adverse reactions.

Nahon/Malchiodi

Conclusions: These data expand our

understanding

of the prediction of treatment

course in late-life depression. The authors

propose that the primary variables of hippocampal volume and cognitive

processing

speed, subsuming other contributing

variables (episodic memory, executive

function, language processing) predict antidepressant

response.

Nahon/Malchiodi

Nahon/Malchiodi

Efficacy of SSRIs on cognition of Alzheimer's disease patients treated with cholinesterase inhibitors.

This study examines the joint effect on cognition of selective serotonin re-uptake inhibitors (SSRIs) and cholinesterase inhibitors (AChEIs) in depressed patients affected by Alzheimer's disease (AD) living at home.

Patients were grouped in three different categories (patients not depressed and not treated with SSRIs, patients depressed and treated with SSRIs, and patients depressed but not treated with SSRIs).

The mean change in MMSE score from baseline to nine months showed that depressed patients not treated worsened in comparison with those not depressed and not treated with SSRIs and patients depressed and treated with SSRI.

In AD patients treated with AChEIs, SSRIs may exert some degree of protection against the negative effects of depression on cognition.

(Rozzini L, International psychogeriatrics, 2010 Feb)

Nahon/Malchiodi

Rozzini R, “Depressione e Demenza: riflessi in uno specchio oscuro”

• La presenza di sintomi depressivi in pazienti con demenza è necessariamente una manifestazione di depressione o piuttosto la normale risposta ad una condizione svantaggiosa?

(13° Congresso AIP, 2013)

Nahon/Malchiodi

M. Rothko “Blue Green and Brown”, 1951

Good News!

• In questo ambito qualsiasi sviluppo della scienza positiva (Evidence based) va contemporaneamente festeggiato ma anche accolto con tranquillo,lungimirante , affettuoso scetticismo , sapendo quanto le scoperte della Scienza si possano poi anche rivelare limitate o fallaci .

Nahon, 2010

Che siano le neuroscienze?

• “Credere alla medicina sarebbe la suprema follia se non crederci non ne costituisse una più grande ,giacchè da quest’accumulo di errori ,alla lunga son venute fuori alcune verità.

• Marcel Proust , Le Coté des Guermantes

Y. Klein “YKB”