Pnie de Quetiapina y Otros Atipicos

QUETIAPINA
Perfil
Psiconeuroinmunoendócrino
ANDREA MARQUEZ LOPEZ MATO

PABLO BERETTA
Instituto de Psiquiatría Biológica Integral
www.ipbi.com.ar
RECEPTOR BINDING Goldstein 1999
Clozapine Seroquel Receptor

M D1 D D1 D2
2 A1, 2 = a1, a2 adrenergic
5HT2A
H1 D1,2 = dopamine
5HT1A
5HT2A
H1 = histamine
5HT1A, 2A = serotonin
H1 A1
M = muscarinic
A2
5HT1A A2
A1
Haloperidol Olanzapine Risperidone

H1 D1 D
D1 D2 A2 H1 1 D2
A1
A1
5HT2A
M
5HT1A
A1
D2 H1 5HT2A
El punto más difícil no es que respondan al tratamiento;
sino que continúen tomando la medicación
Lieberman, 90
Tolerabilidad
Eficacia
Seguridad
Efectividad al
Tratamiento
Adherencia/
Continuidad
Ninguna píldora puede ayudarme a lidiar con el problema de no querer

tomarlas Godwin and Jamison, 90
.
SHIFT IN RISK PERCEPTION
Prior Safety Concerns Current Safety Concerns
Diabetes
Neurologic Side Effects
EPS + TD Weight Gain Hyper

Glycemia CVD
Insulin
Weight
Resistance
Gain
Insulin
Resistance Hyper- EPS
lipidemia QTc
CVD
Dyslipidemia
QTc Hyper-
glycemia
THE CONTINUUM OF CARE
Efficacy
Positive symptom relief Negative symptom relief
Hostility, aggression Improve mood and
Smooth IM to PO transition depressive symptoms
Alleviation of comorbid Cognitive improvement
depressive/manic
Control symptoms
Behavior
(agitation) Relapse Prevention
1-3 days 7-14 days 6+ months
Acute dystonia EPS TD
Sedation Drug-drug interactions Hyperprolactinemia
Orthostasis QTc prolongation Weight gain
QTc prolongation Hyperglycemia
QTc prolongation
Safety
SIDE EFFECTS
Maudsley Hospital Prescribing Guidelines

PNIE DEL TRATAMIENTO AP
• Desórdenes por extrapiramidalismo
• Desórdenes por hiperprolactinemia
• Desórdenes endócrinos varios
• Desórdenes de aumento de peso
• Desórdenes del metabolismo hidrocarbonado
• Desórdenes del metabolismo lipídico
• Desórdenes del balance hídrico
• Desórdenes metabolismo hepático y cardíaco
• Desórdenes hematológicos e inmunes
• Desórdenes de la sexualidad
• Teratogénesis, carcinogénesis y otros
Lopez Mato. 2002
Lopez Mato. 2002
GRADO DI OCCUPAZIONE RECETTORIALE D2 NELLO
STRIATO y EFFETI COLATERALI
A dosaggi terapeutici, gli APT presentano un grado di

occupazione dei recettori dopaminergici D2 compreso
tra il 70% e l’ 89%
occupazione recettoriale
efficacia antipsicotica 60-70%
iperprolattinemia > 70%
EPS > 80%
L’efficacia clinica degli APT è inevitabilmente associata

all’iperprolattinemia
L’aumento della prolattina è un marker della azione dei farmaci APT
MOVIMIENTOS ANORMALES POR AP:
BUTIROFENONAS
SULPIRIDA
AMISULPRIDE
RISPERIDONA
PROMAZINICOS
ARIPRIPAZOL
OLANZAPINA
ZIPRASIDONA
CLOZAPINA
QUETIAPINA
Lopez Mato A., 2003
PARKINSONISMO
• Parkinsonismo Motor
– EPS
– Distonía
– Diskinesia tardía
• Parkinsonismo Cognitivo
– Pensamiento enlentecido y pobre
– Sentimiento de vacío
– Dificultades de concentración
Gerlach 98
PARKINSONISMO
• Parkinsonismo Social
– Falta de iniciativa
– Disminución de las energías
– Pobreza de contactos sociales
• Parkinsonismo Emocional
– Indiferencia emocional
– Anhedonia
– Falta de placer en las actividades Gerlach 98
LOW EPS RISK
Improved
compliance
Negative Lower tardive
symptoms dyskinesia risk
benefit
EPS
Advantage
Cognitive Fewer motor
advantage side effects
Less
dysphoria
Jibson and Tandon 1998
SIMPSON-ANGUS (SEP)
CATIE
100
90
80
70
60
50
%
40
30
20
8% 6% 8% 9%
10 4%
0
OLZ PER QUET RIS ZIP
Lieberman JA, et al. N Engl J Med. 2005;353(12):1209-1223.
Lopez Mato. 2002
AUMENTO PROLACTINA POR AP:
BUTIROFENONAS
SULPIRIDA
AMISULPRIDE
RISPERIDONA
PROMAZINICOS
ZIPRASIDONA
ARIPRIPAZOL
OLANZAPINA
QUETIAPINA
CLOZAPINA
Lopez Mato A., 2003
HYPERPROLACTINEMIA
Sexual
dysfunction
Gynaecomastia Amenorrhoea
Prolactin
Impotence elevation Osteoporosis
Breast
Galactorrhoea
enlargement
Data from Arvanitis et al 1997

LA PROLACTINA ES MAS QUE
UNA HORMONA DE MATERNAJE
• Función en “coping” (afrontamiento) al stress

• Función metabólica (hormona anabólica)
• Función sobre SNC (crecimiento dendrital y
sinaptogénesis)
• Función sobre inmunomodulación
• Función sobre conductas sexual y maternal
Illa G . Lopez Mato A . Psiconeuroinmunoendocrinologia. 2002

BUT PROLACTIN IN UNMEDICATED SCHIZOPHRENIC
PRL levels are not elevated in un medicated

schizophrenic patients
But they show a phase advance of circadian serum

prolactin secretion with the peak serum PRL level
being reached 1.5 hours earlier
Daytime PRL secretion does not appear to be

enhanced
However, it has been suggested that PRL in the normal
range may be correlated to different subgroups of disease
PRL IN SCHIZOPHRENIA SUBTYPESF
M
The “normal” range of

serum prolactin levels
seems to obscure
significant differences
between specific F
groups of schizophrenia
M
patients
M. Segala, A. et al. Serum prolactin levels in unmedicated first-episode and recurrent

schizophrenia patients: a possible marker for the disease’s subtypes Psychiatry Research 127
(2004) 227– 235
QUETIAPINE AND PROLACTIN
Data from Arvanitis et al 1997
Mean 20 **
change in
prolactin
levels 15
(µg/L)
from
baseline 10
at
endpoint 5
-5 Placebo 75 150 300 600 750 Haloperidol

12 mg/day
Seroquel (mg/day)
**p<0.01 vs placebo
NORMALISATION OF PREVIOUSLY
ELEVATED PROLACTIN LEVELS
Seroquel Haloperidol
LSM change 15 up to 800 mg/day up to 20 mg/day
in prolactin (n=429) (n=320)
levels (µg/L) 10
from baseline
to end of
treatment 5
-5
-10 ***
Meta-analysis of 3 double-blind, randomised trials

***p<0.001 vs haloperidol Data on file - AstraZeneca
HYPERPROLACTINEMIA
Although an elevation of prolactin levels was

not demonstrated in clinical trials with
SEROQUEL, increased prolactin levels were
observed in rat studies with this compound,
and were associated with an increase in
mammary gland neoplasia in rats.
De Seroquel
PRL AND BREAST CANCER
Two studies (in 1999 and 2004), from Hankinson's group demonstrated
a clear correlation between PRL levels and breast cancer risk in
>30,000 postmenopausal women with 306 and 851 breast cancers respectively
Women with PRL levels in the higher quartile of the normal range
had an increased risk (by a factor of 2) of developing breast cancer,
compared to patients with PRL levels in the lower quartile of the normal range)
This risk mainly affected ER+ tumors (RR of 1.78; 95% CI 1.28-2.5)
and ER+/PR- tumors (RR 1.94; 95% CI 0.99-3.78)
Currently we don’t know whether hyperprolactinemic patients are at

high risk of developing cancers (no large scale studies)
- Hankinson SE, et al. 1999, Plasma prolactin levels and subsequent risk of breast
cancer in postmenopausal women. J Natl Cancer Inst 91:629-634
- Tworoger SS, et al. 2004 Plasma prolactin concentrations and risk of
postmenopausal breast cancer. Cancer Res 64:6814-6819
PRL AND PROSTATE CANCER
One recent study, involving ~ 30,000 men including 144 prostate
cancers
(the Northern Sweden Health and Disease Cohort), concluded that:
there is no correlation between PRL levels and the risk to develop
prostate cancer
There is no epidemiological study investigating PRL as a possible
risk factor for developing prostate hyperplasia.
Only one recent report is available.
It is a prospective, case-control
study involving only 20 men with prolactinoma in which
no correlation between hyperprolactinemia and prostate hyperplasia
was found
- Stattin P, et al. 2001 Plasma prolactin and prostate cancer risk: A prospective study. IJ Cancer
92:463-465
- Colao A, et al. 2004 Prolactin and prostate hypertrophy: a pilot observational, prospective,
study in men with prolactinoma. J Clin Endocrinol Metab 89:2770-5
Lopez Mato. 2002
HIPOTIROIDISMO
Quetiapine is known to have adverse effects on
thyroid function.
In clinical trials, about 0.4% (10/2386) of patients
treated with quetiapine experienced TSH elevations,
and 6 of these sujects required thyroid hormone
supplementation.
The mechanism of action by which quetiapine causes
hypothyroidism is unknown.
Quetiapine-induced hypothyroidism. Sriram Ramaswamy, MD, Zakaria Siddiqui,

MD, Sahdev Saharan, MD, Teri L. Gabel, PharmD, BCPP, and Subhash C.
Bhatia, MD. Omaha, Nebraska, USA
It is expected that TT[4] levels will decrease during
quetiapine treatment, and this may possibly be related
to competitive metabolism of thyroid hormones and
quetiapine by UDP-glucuronosyltransferase.
KELLY Deanna L.; CONLEY Robert R.;, Maryland Psychiatric Research Center,
University of Maryland School of Medicine, Baltimore, ETATS-UNIS
Other mood stabilizers like valproate or lithium appear to affect

TSH or hormone levels, and when combined
with quetiapine may affect thyroid function more
strongly than any single drug.
Patients taking lithium and either valproate or quetiapine should
have serum TSH monitored every three months for the first year in
treatment.
Aaron Levin. Commonly prescribed psychopharmacological agents can cause a range of side
effects in the endocrine system, but they can be managed by aware clinicians. Psychiatric
News April 15, 2005. Volume 40 Number 8, p. 53.
Cortisol decreased after quetiapine administration from
time 150 min to time 240 min.
ACTH secretion showed no difference compared to

placebo.
There was a late increase in growth hormone secretion,

significant in comparison with placebo only at time 210
min.
Neuroendocrine effects of quetiapine in healthy volunteers
Alexandro de Borja Gonçalves Guerra, Saulo Castel
The International Journal of Neuropsychopharmacology (2005), 8: 49-57
Lopez Mato. 2002
CLINICA DIARIA
AUMENTO DE PESO POR AP:
CLOZAPINA
OLANZAPINA
RISPERIDONA
QUETIAPINA
ZIPRASIDONA
HALOPERIDOL
ARIPIRAZOL
Nashraldam H, Korn M, Metabolic Disorders in Schizophrenic. Relation to AA
Treatment. Schizophrenia Medscape Expert Columm, 28-7-04
AUMENTO DE PESO
• Mayor incidencia en mujeres

• Mayor incidencia en bipolares
• Mayor aumento cuanto menor BMI
• No dosis dependiente
• Historia personal o familiar de
obesidad
• El aumento de peso correlaciona con
la mejoría sintomática, sobre todo
con la resocialización
• Desde la era preneuroléptica se

correlaciona aumento de peso con
mejoría de la psicosis
PESO Y AA
Liberación de TNF-a Reducción en
y otras Citoquinas el Metabolismo Acción en Hipotálamo
Basal lateral y ventromedial
MECANISMOS
Reducción de Acatisia Antagonismo Receptores
INVOLUCRADO H1 y 5-HT2c
S EN EL
AUMENTO DE
PESO
Cambios en la
Insulinoresistencia Sensibilidad a
la Leptina
1 Baptista T. Acta Psychiatr Scand. 1999;100(1):3-16. 2 Cohen S, et al. J Clin Psychiatry. 2001;62(2):114-116. 3 Heiman ML, et al.
Presented at: 154th APA Annual Meeting; May 5-10, 2001; New Orleans. 4 Mercer LP, et al. J Nutr. 1994;124(7): 1029-1036. 5 Reynolds
GP, et al. Lancet. 2002;359(9323):2086-2087. 6 Simansky KJ. Behav Brain Res.1996;73(1-2):37-42. 7 Stanton JM. Schizophr Bull.
1995;21(3):463-472. 8 Tecott LH, et al. Nature. 1995;374(6522):542-546. 9 Virkkunen M, Pharmacopsychiatry. 2002;35(3):124-126. 10
Lopez Mato el al, VerteX .2003
PESO Y DOSIS
Change in 5
mean
weight from 4
baseline
3 300 mg >300-500 mg >500 mg
(kg)
2
1
-1
-2
343 407 327
Mean duration of
treatment (days) (n=103) (n=94) (n=174)
Brecher et al 2000
Patients
PESO Y TTO CRONICO
80
(%)
70
60
50
40
30
20
10
0
Unfavourable Favourable Unchanged Unfavourable
53 weeks decrease shifta increase
Dose up to 800 mg/day
Shift in BMI category from baseline
(n=112)
aFavourable increase or decrease Data on file - AstraZeneca
TTO CRONICO Y OBESIDAD SEVERA
Patients 80
(%)
70
60
50
40
30
20
10
0
Unfavourable Favourable Unchanged Unfavourable
53 weeks decrease decrease increase
(n=20) Shift in BMI category from baseline
Dose up to 800 mg/day Data on file - AstraZeneca
Lopez Mato. 2002
LABORATORY ASSESSMENTS
Seroquel XR
Seroquel
Mean Change IR 400
From Baseline PBO 400 mg 600 mg 800 mg mg
(SD) (n=118) (n=113) (n=113) (n=121) (n=123)
Hb1Ac (%) -0.02 (0.26) 0.03 (0.26) -0.01 (0.29) 0.07 (0.30) -0.01 (0.25)
Glucose (mmol/L) 0.02 (0.94) -0.04 (0.95) 0.09 (0.81) -0.08 (0.76) -0.08 (0.79)
2.14 7.39 31.69
Insulin (pmol/L) 0.48 (93.92)21.99 (127.41)
(106.29) (97.70) (139.53)
Total cholesterol
-0.15 (0.80) 0.17 (0.85) 0.25 (0.93) 0.17 (0.85) 0.36 (0.82)
(mmol/L)
LDL cholesterol
-0.10 (0.66) 0.07 (0.67) 0.22 (0.74) 0.04 (0.76) 0.25 (0.66)
(mmol/L)
HDL cholesterol
-0.01 (0.24) 0.01 (0.23) -0.02 (0.26) -0.01 (0.25) 0 (0.28)
(mmol/L)
Triglycerides (mmol/L) -0.11 (0.78) 0.17 (0.92) 0.15 (1.12) 0.31 (1.11) 0.32 (0.85)
Lopez Mato. 2002
CHOLESTEROL AND
TRIGLYCERIDE ELEVATIONS:
In schizophrenia trials, Quetiapine-treated

patients had increases from baseline in
cholesterol and triglyceride of 11% and 17%,
respectively, compared to slight decreases
for placebo patients.
These changes were only weakly related to
the increases in weight observed in
Quetiapine-treated patients.
Lopez Mato. 2002
CLINICA DIARIA
RIESGO DE SIADH POR AP:
PROMAZINICOS
ZIPRASIDONA
QUETIAPINA ????
CLOZAPINA
OLANZAPINA
OTROS ANTIPSICOTICOS
BUTIROFENONAS
Lopez Mato A, 2003
POLIDIPSIA PSICOGENA
(Intoxicación Hídrica)
• Frecuente en esquizofrenia crónica
– Con hiponatremia (SIADH)
– Sin hiponatremia
• Exacerbación psicótica con metilfenidato aumenta
secreción de ADH
– NL aumentan disfunción por acción directa sobre
ADH; acción de AA se desconoce
• Complicación severa: convulsiones
• Sospecha: aumento diurno > 2 kilos
Lopez Mato. 2002
Recently risperidone and quetiapine have been
reported to cause hypokalaemia due to cellular shift.
Norden A. Laboratory Endocrinology: Investigation of hypokalaemia. Department of
Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge., UK
Report of an elderly man who developed hyponatremia after treatment with

quetiapine
Atalay, Ayce MD; A Case of Syndrome of Inappropriate Secretion of Antidiuretic Hormone

in Elderly Patient Secondary to Quetiapine. Southern Medical Jour. 2007.
Het syndroom van inadequate secretie van antidiuretisch hormoon (SIADH)

tijdens het gebruik van de antipsychotica haloperidol en quetiapine
Van den heuvel OA ; Bet P. M. Nederlands tijdschrift voor geneeskunde 2006,

Lopez Mato. 2002
RIESGO DE EVENTOS
HEPATOTOXICOS POR AP
CARBAMACEPINA
VALPROICO
PROMAZINICOS
OLANZAPINA
QUETIAPINA
LITIO Lopez Mato A., 2003

TRANSAMINASE ELEVATIONS
Asymptomatic, transient and reversible elevations -
-In schizophrenia trials, elevations of > 3 times :

6% for Quetiapine compared to 1% for placebo.
- In acute bipolar mania trials, elevations of > 3 times:
1% both for Quetiapine and placebo.
No se necesita interrumpir tratamiento

De Seroquel
RIESGO DE EVENTOS CARDIOLOGICOS
POR AP:
TIORIDAZINA
ZIPRASIDONA
SERTINDOL
PROMAZINICOS
QUETIAPINA
OLANZAPINA
Lopez Mato A., 2003
AA Y QT
Mean QTc 40 aPfizer
study 54 baseline correction
change 35 Doses are highest total daily doses evaluated
from
30
baselinea
(msec) 25
20
15
10
5
0
-5 Olanzapine Risperidone Seroquel Haloperidol ZiprasidoneThioridazine
20 mg 16 mg 750 mg 15 mg 160 mg 300 mg
(n=24) (n=25) (n=27) (n=27) (n=31) (n=30)
Pfizer Study 54, FDA Psychopharmacological Drug Advisory

Committee 19th July 2000
CEREBROVASCULAR
ADVERSE EVENTS
Class warning for elevated risk of

cerebrovascular adverse events
Risperidone (3.8%) vs. Placebo (1.5%); N=1230

Olanzapine (1.3%) vs. Placebo (0.4%); N=1882
Aripiprazole (1.3%) vs. Placebo (0.6%); N=938
Quetiapine (0.3%) vs. Placebo (1.9%); N=568
NEW WARNING
- 17 PCTs reviewed enrolling 5377 elderly pts with dementia related behavioral
disorders (3611 drug, 1766 placebo)
-Rate of death:
- drug treated patients : 4.5%
- placebo group: 2.6%
-Risk of death: 1.6 to 1.7 times bigger
-Cause of death:
- heart related or infectious
Six drugs involved: aripiprazole, olanzapine, risperidone, quetiapine,

ziprasidone, haloperidol, clozapine, and olanzapine/fluoxetine
Atypical antipsychotics used to treat dementia-related psychosis carry an “increased

risk of death compared with placebo” FDA Warning on Mortality. April 11, 2005
Lopez Mato. 2002
RIESGO DE EVENTOS
HEMATOLOGICOS POR AP
CLOZAPINA
PROMAZINICOS
CARBAMACEPINA
LITIO
QUETIAPINA
Lopez Mato A., 2003
NEUTROPHIL COUNTS
Seroque
Seroquel XR
l IR 400
Neutrophil PBO 400 mg 600 mg 800 mg mg
Count* (n=118) (n=113) (n=113) (n=121) (n=123)
<0.5 x 109 cells/L,
0 0 0 1† 0
na
<1.5 x 109 cells/L,
0 2 0 3 3
na
aResults are presented as number of patients

*Neutropenia defined as a low cell count <1.5 x 109 cells/L
†One patient with one non-serious AE (neutrophil count decreased) potentially
related to agranulocytosis (defined as a cell count <0.5 x 109 cells/L) was

reported and led to discontinuation from the study
Lopez Mato. 2002
RIESGO DE DISFUNCION SEXUAL
ANTICOLINERGICOS
CLOZAPINA
ZIPRASIDONA
RISPERIDONA
BUTIROFENONAS
QUETIAPINA
OLANZAPINA
ARIPRIPAZOL
Lopez Mato A., 2003
SEXUAL DYSFUNCTION
Randomized open-label study of the impact of quetiapine versus risperidone
on sexual functioning.
(mayor to risperidone)
Knegtering R, Castelein S, Bous H, Department of Psychiatry, University Hospital Groningen,

The Netherlands.
One case of priapism in a patient receiving Quetiapine has been reported

prior to market introduction.
While a causal relationship to use of Quetiapine has not been established,
other drugs with alpha-adrenergic blocking effects have been reported to
induce
priapism, and it is possible that Quetiapine may share this capacity.

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QUETIAPINA

ANDREA MARQUEZ LOPEZ MATO

Clozapine Seroquel Receptor

Haloperidol Olanzapine Risperidone

Ninguna píldora puede ayudarme a lidiar con el problema de no querer

EPS + TD Weight Gain Hyper

Maudsley Hospital Prescribing Guidelines

A dosaggi terapeutici, gli APT presentano un grado di

L’efficacia clinica degli APT è inevitabilmente associata

Data from Arvanitis et al 1997

• Función en “coping” (afrontamiento) al stress

Illa G . Lopez Mato A . Psiconeuroinmunoendocrinologia. 2002

PRL levels are not elevated in un medicated

But they show a phase advance of circadian serum

Daytime PRL secretion does not appear to be

The “normal” range of

M. Segala, A. et al. Serum prolactin levels in unmedicated first-episode and recurrent

-5 Placebo 75 150 300 600 750 Haloperidol

Meta-analysis of 3 double-blind, randomised trials

Although an elevation of prolactin levels was

Currently we don’t know whether hyperprolactinemic patients are at

Quetiapine-induced hypothyroidism. Sriram Ramaswamy, MD, Zakaria Siddiqui,

Other mood stabilizers like valproate or lithium appear to affect

ACTH secretion showed no difference compared to

There was a late increase in growth hormone secretion,

• Mayor incidencia en mujeres

• Desde la era preneuroléptica se

In schizophrenia trials, Quetiapine-treated

Report of an elderly man who developed hyponatremia after treatment with

Atalay, Ayce MD; A Case of Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Het syndroom van inadequate secretie van antidiuretisch hormoon (SIADH)

Van den heuvel OA ; Bet P. M. Nederlands tijdschrift voor geneeskunde 2006,

LITIO Lopez Mato A., 2003

-In schizophrenia trials, elevations of > 3 times :

No se necesita interrumpir tratamiento

Pfizer Study 54, FDA Psychopharmacological Drug Advisory

Class warning for elevated risk of

Risperidone (3.8%) vs. Placebo (1.5%); N=1230

Six drugs involved: aripiprazole, olanzapine, risperidone, quetiapine,

Atypical antipsychotics used to treat dementia-related psychosis carry an “increased

aResults are presented as number of patients

related to agranulocytosis (defined as a cell count <0.5 x 109 cells/L) was

Knegtering R, Castelein S, Bous H, Department of Psychiatry, University Hospital Groningen,

One case of priapism in a patient receiving Quetiapine has been reported

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