Gli antipsicotici nel paziente

anziano: problemi aperti

Liliana Dell’Osso

Direttore Clinica Psichiatrica

Università di Pisa

Introduction

Psychoses: presence of hallucinations and/or delusions

Psychotic symptoms cause substantial psychosocial

morbidity, frequently affecting patients’ relationships as

well as their ability to care for themselves and other

aspects of their lives.

Buono

importanza di genere ed età

dis raggruppati in base agli ipotetici meccanismi comuni

introdotta componente dimensionale della diagnosi

(spettro sottosoglia)

Cattivo

non corrisponde alle aspettative dei clinici

maggior parte delle modifiche sono operazioni di cosmesi

fallito l’intento di tenere conto nella diagnosi di marker

neurobiologici o della patofisiologia del disturbo

Brutto

in futuro dovremo affidarci solo alla descrizione del

disturbo per definire le entità di malattia psichiatriche,

come è da più di un secolo

79

• Irritabilità

• Labilità emotiva

• Sintomi di panico

• Frequenti crisi di pianto

• Somatizzazioni

• Agitazione psicomotoria

• Delirio di gelosia e persecuzione

• Turpiloquio

A.B. ♀, 79 anni, sposata

Diagnosi: disturbo delirante diabete mellito, obesità, ipoacusia

79

A.B. ♀, 79 anni, sposata

Menopausa Lutto

60 50

Diagnosi: disturbo delirante disturbo bipolare II

diabete mellito, obesità, ipoacusia

79

A.B. ♀, 79 anni, sposata

Menopausa Lutto

60 50

Diagnosi: disturbo delirante disturbo bipolare II disturbo di panico, uso di sostanze

diabete mellito, obesità, ipoacusia

Somatizzazioni

BDZ BDZ Abuso di oppioidi

79

Menopausa Lutto

60 50

Diagnosi: disturbo delirante disturbo bipolare II disturbo di panico, uso di sostanze disturbo neurocognitivo vascolare con dist comportamento

diabete mellito, obesità, ipoacusia

Somatizzazioni

BDZ BDZ Abuso di oppioidi

Deficit memoria

a breve termine

Compromissione

orientamento ST

Alterazioni del

pattern ipnico

A.B. ♀, 79 anni, sposata

A.B. ♀, 79 anni, sposata

disturbo neurocognitivo vascolare

disturbo delirante

uso di sostanze

disturbo di panico

disturbo bipolare II

Durante la degenza:

•Timoregolatori (Acido Valproico)

•Antipsicotici tipici (Perfenazina)

atipici (Risperidone)

•Ipnoinducenti (Idrossizina)

Terapia alla dimissione:

•Lansox 30 mg

•Lasix 25 mg

•Cardioaspirin 100 mg

•Depakin 500 mg

•Risperdal 1 mg

•Atarax 50 mg

•Terapia insulinica (novorapid, lantus)

Prevalence of Psychosis in Elderly Persons

Community: 0.2% to 4.7%;

Age 85+ (without dementia): 7.1% to 13.7%

Age 95+(without dementia): 7.4%

Nursing Homes: 10% to 62%

Key Points

1. In older adults, for all conditions consider

comorbidity

2. Any new psychiatric conditions or change in

symptoms must assume physical cause until

proven otherwise

0

Early onset Bipolar Disorder

More severe episodes over time

History of mixed mania (onset and index episode)

Comorbid substance and alcohol abuse

History of mood incongruent delusions

History of suicide attempts

Resistance to pharmacotherapy

Poor insight

Poor outcome

Poor prognosis

Bipolar Disorder + Panic Disorder

1. Psychosis can be primary (due to psychiatric

disorder) or secondary (due to medical/

neurological disorder)

2. There is no reliable pathognomonic signs to

distinguish primary or secondary psychosis

(need to rule out secondary causes)

Key Points

A) Primary psychotic disorders:

Schizophrenia and related disorders

Schizophrenia

Schizoaffective disorder

Schizophreniform disorder

Delusional disorder

Brief psychotic disorder

Affective psychoses

Bipolar disorder with psychotic features

Unipolar depression with psychotic features

B) Secondary psychotic disorders:

Psychotic symptoms associated with dementia

Alzheimer’s Disease with psychoses

Vascular dementia with psychoses

Lewy Body Disease with psychoses

Other dementing disorders with psychoses

Psychotic symptoms during delirium

Psychotic symptoms associated with medications and substance abuse

Psychotic symptoms due to medical and surgical disorders

Classification of Psychotic Disorders

Etiologies of Psychoses in Older Adults

(order of frequency)

Alzheimer’s disease and other dementias (40%)

Depressive disorder (33%)

Medical/toxic causes including substances (11%)

Delirium (7%)

Bipolar Disorder (5%)

Delusional disorder (2%)

Schizophrenia spectrum disorders (1%)

Manepalli et al, 2007

Psychotic disorders in old age have more toxic (drugs), metabolic and structural (brain lesions, tumors) associations and a greater association with dementia.

Certain secondary psychotic disorders (e.g., delirium and psychosis due to a general medical condition) can be fatal and are at higher risk of serious iatrogenic damage (incorrect doses, medications)

Classification of Psychotic Disorders

Risk Factors for Psychosis in the Elderly

comorbid psychiatric illnesses (esp. dementia and delirium)

genetic predisposition

female

social isolation

sensory deficits (visual and hearing impairment)

cognitive changes

polypharmacy

certain premorbid personality traits

poor caretaker relationships

bedridden condition

early life trauma

substance abuse

Prior psychiatric history , diagnoses, or psychotic symptoms?

Yes

No Cognitive decline?

Secondary psychotic disorder?

Underlying medical

Conditions? Chemically induced?

Primary psychotic

disorders

Dementia with

psychosis

Primary psychotic

disorders

Yes No

No No

Decision tree for determining etiology of psychotic

symptoms in elderly patients

Primary psychotic disorders

Affective symptoms predominant?

Yes No

Mania?

Hypomania?

Depression

Only?

Only

delusions?

Delusions and

Hallucinations?

1- 6 month

duration?

Unipolar

depression

Schizophrenia

More than 6

months duration?

Delusional

disorder

Bipolar

disorder

Schizophreniform

disorder

Less than 1

month duration?

Brief psychotic

disorder

Decision tree for determining etiology of psychotic

symptoms in elderly patients

Onset of Psychotic Symptoms

Early-onset vs late-onset: different risk factors and typical signs and symptoms

Late-onset psychosis:

• Female: 75%, 70s

• Alzheimer: most common cause

• New onset of mania: high rates of medical and neurological disease, higher risk of mortality

• Identifiable structural brain abnormalities (underlying brain pathology)

Psychosis due to Prescription Drugs

Dementia: sensitive to medications with direct or

indirect anticholinergic properties

Tactile hallucination: most commonly in toxic

and metabolic disturbances or drug withdrawal

states

Medication and Substance-induced

Psychotic Symptoms in the Elderly

Prescription medications

Antiparkinsonian drugs

L-dopa or carbidopa

Amantadine

Bromocriptine

Anticholinergic and

antihistaminic agents

Diphenhydramine

Hydroxizine

Tricyclic antidepressants

Cimetidine

Stimulants

Methylphenidate

amphetamine

Thyroid

Ephedrine

Over-the-counter medications

Antihistaminics

Cold medications

Cough suppressants

Sleep aids

Allergy medications

Substances of abuse

Alcohol

Cocaine

Opioids

Benzodiazepines

Cannabis

Medication and Substance-induced Psychotic

Symptoms in the Elderly

Prescription medications

Analgesics and antiinflammatory drugs Indomethacin

Antineoplastic agents

Oral or parenteral steroids

Prednisone

Dexamethasone

Antiarrythmic and cardiac drugs

Digitalis

Quinidine

Procainamide

Propranolol

Sedative-hypnotics

Benzodiazepines

Barbiturates

Chloral hydrate

Medical causes of psychosis

Neurological: stroke, brain tumors,multiple sclerosis

Endocrine: hypothyroidism, hyperthyroidism, adrenal failure,

Cushing's syndrome, hypo-/hyperparathyroidism

Nutritional deficiency: vitamin B12 deficiency

Electrolyte disturbances: hypo-/hypercalcemia, hypernatremia,

hyponatremia, hypokalemia, hypo-/hypermagnesemia, and

hypophosphatemia,

Infectious: viral encephalitis, HIV, malaria, Lyme disease,

syphilis

Hypoglycemia, hypoxia, and failure of the liver or kidneys

Physiological changes in elderly persons associated with

altered pharmacokinetics

Organ system Change Pharmacokinetic consequence

Circulatory system

Decreased concentration of

plasma albumin and increased

alpha1-acid glycoprotein

Increased or decreased free

concentration of drugs in plasma

Gastrointestinal tract Decreased intestinal and

splanchnic blood flow

Decreased rate of drug

absorption

Kidney Decreased glomerular filtration

rate

Decreased renal clearance of

active metabolites

Liver

Decreased liver size; decreased

hepatic blood flow; variable

effects on cytochrome P450

isozyme activity

Decreased hepatic clearance

Muscle Decreased lean body mass and

increased adipose tissue

Altered volume of distribution of

lipid-soluble drugs leading to

increased eliminated half-life

Antipsychotics

FDA Advisory (2005) warning of the increased risk of death due to cardiovascular events or infections in demented patients treated with “atypical” antipsychotics

relative to placebo (1.5 to 1.7 times).

“Novel” preferred over “conventional” antipsychotics • Less likely to cause EPS and can be used in PD

• Novel tend to cause anticholinergic effects less frequently than the older drugs. One exception is perphenazine that seem to have particularly low incidence of these effects (Ozbilen and Adams, 2009).

Antipsychotics - uses

Late-life psychoses

• Schizophrenia

• Dementia

• Mood Disorders

• Delusional Disorder

Mood stabilizers

Augmentation treatment of so called “resistant depression”

Antipsychotics and Aging

Clozapine: agranulocytosis and delirium (increase with age), CV side effects (othostatic hypotension, tachycardia, rarely myocarditis), sedation, risk of seizures, anticholinergic toxicity

Risperidone: dose-dependent EPS, orthostasis, peripheral edema

Olanzapine: somnolence, unsteady gait, falls

Quetiapine: sedation, orthostasis (esp. higher dose)

Ziprasidone: QTc prolongation and limited data

Antipsychotics and Aging

Weight gain: conventional and atypical antipsychotics

Meyer et al, 2008

Antipsychotics and Aging

New-onset diabetes mellitus:

Risperidone: lower risk compared with clozapine,

olanzapine, and quetiapine in patients age 40 and older

(Sernyak et al 2002)

Elderly: use lower dose, evaluate concomitant

medications and excretion of psychotropic drugs more

sensitive to side effects

Risk of Tardive Dyskinesia

Conventional antipsychotics in elderly (esp. dementia):

very high incidence of tardive diskinesia

(> 1 yr: 29%; > 3 yr: 60%)

• Atypical antipsychotics: tardive diskinesia significantly

lower

• Early development of EPS is a strong predictor for

tardive diskinesia in the elderly.

• Perphenazine unexpectedly showed comparable

levels of effectiveness and produced no more EPS

than the other agents (Theo et al., 2007)

Harv Rev Psychiatry September/October 2007

The CATIE (Clinical Antipsychotic Trials for Intervention

Effectiveness) Schizophrenia Trial was designed to examine

fundamental issues about second-generation antipsychotic (SGA)

medications (olanzapine, risperidone, quetiapine, and ziprasidone),

their relative effectiveness and their effectiveness compared to a

first-generation antipsychotic (FGA), perphenazine.

Materiale di Training da utilizzare esclusivamente per esigenze didattiche. Ne è vietata la distribuzione.

Premessa: • Atipici hanno promesso riduzione discinesia, EPS, e

sintomi negativi

• Allarme su aumento di peso e altri disturbi metabolici associati agli atipici

• Elevato costo e volumi di vendita degli atipici

• Elevata incidenza di malattie cardiovascolari tra gli schizofrenici

Dubbi e controversie sugli atipici:

The CATIE (Clinical Antipsychotic Trials for

Intervention Effectiveness) Schizophrenia Trial

• come si confrontano l’uno con l’altro?

• e con i tipici?

• sono costo-efficaci, visto l’alto costo?

Materiale di Training da utilizzare esclusivamente per esigenze didattiche. Ne è vietata la distribuzione.

Perfenazina è stata efficace come tre degli altri agenti

atipici (quetiapina, risperidone, ziprasidone) ed è stata

ugualmente ben tollerata come molti dei nuovi agenti

Risultato dovuto al meccanismo d’azione di perfenazina:

ridotta affinità per il recettore sottotipo D2 della dopamina

e maggiore affinità per i recettori serotoninergici 5-

HT2A IL PIU’ ATIPICO TRA I TIPICI

Lo studio CATIE ha messo in evidenza le aspettative non

corrisposte degli antipsicotici di seconda generazione

CONCLUSIONI

The CATIE (Clinical Antipsychotic Trials for

Intervention Effectiveness) Schizophrenia Trial

Conclusion

Psychotic symptoms in the elderly: highly prevalent,

substantial morbidity and mortality, premature

institutionalization, economic burden, treatable (early therapy)

Etiology: varied widely

Therapy: psychosocial interventions, antipsychotics (not

always true that atypical is better than conventional)

“Scientific evidence now places many, if not

most, disorders on a spectrum with closely

related disorders that have shared symptoms,

neural substrates, genetic and environmental

risk factors, (perhaps most strongly established

for a subset of anxiety disorders by

neuroimaging and animal models)...”

“In short, we have come to recognize that the

boundaries are more porous than originally

perceived”

Spectrum in DSM-5

DSM-5

Grazie per l’attenzione

Acute Myocardial Ischemia/Period after

Myocardial Infarction

Avoid using medications that cause hypotension, i.e.

phenothiazines, clozapine, and tricyclic antidepressants.

Avoid high dose antipsychotics. They can cause orthostatic

hypotension and tachycardia, besides having a direct cardiac

muscle suppressant effect in patients after myocardial

infarction.

Clozapine should be started slowly and with caution less than a

year after myocardial infarction or in cardiac disease;

olanzapine may be a safer alternative in the acute period after

myocardial infarction.

Stable Ischemic Heart Disease

Avoid using drugs causing orthostatic hypotension (e.g,

trazodone, quetiapine, etc), which may exacerbate angina.

Avoid using drugs causing tachycardia, for example,

phenothiazines, clozapine.

Effect of Psychotropics on QTc*

Low-No effect

Low-moderate

effect

Moderate effect

High effect

Olanzapine

Amisulpiride

Sulpiride

Aripiprazole

Asenapine

SSRIs (except citalopram)

Reboxetine

Nefazodone

Mirtazepine

MAOIs

Carbamazepine

Gabapentin

Lamotrigine

Valproate

Benzodiazepines

Clozapine

Haloperidol

Risperidone

Citalopram

Venlafaxine

Trazodone

Lithium

Chlorpromazine

Quetiapine

Ziprasidone

Zotepine

TCAs

IV antipsychotic

Thioridazine

Pimozine

Sertindole

Take a careful cardiac history, remember to ask

for a family history of syncope or sudden cardiac

death.

Palpitations, presyncope or syncope,

spontaneously or in response to stress, shock or

exertion, should prompt a cardiac referral, even in

the presence of normal electrocardiography.

Long QT

Long QT

Perform a careful physical examination

Perform a 12 lead electrocardiogram. Bear in

mind that the presence of a normal QTc does not

exclude the possibility of a QT interval anomaly.

Take blood for serum potassium, calcium,

magnesium, and thyroid hormone estimation.