quetiapina perfil psiconeuroinmunoendócrino andrea marquez lopez mato pablo beretta instituto de...
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QUETIAPINAPerfil
Psiconeuroinmunoendócrino
ANDREA MARQUEZ LOPEZ MATOPABLO BERETTA
Instituto de Psiquiatría Biológica Integralwww.ipbi.com.ar
RECEPTOR BINDINGGoldstein 1999
D1 D2
5HT2A
5HT1A
A1
A2
H1
SeroquelD1 D2
5HT2A
5HT1A
A2
H1
MClozapine
A1
D1 D2
5HT2A
A1
H1
M
Olanzapine
Receptor
A1, 2 = 1, 2 adrenergic
D1,2 = dopamine
H1 = histamine
5HT1A, 2A = serotonin
M = muscarinic
D1
D2
5HT1A
A1
HaloperidolH1 D2
5HT2A
A1
A2H1
RisperidoneD1
Eficacia Tolerabilidad Tolerabilidad SeguridadSeguridad
Adherencia/Continuidad
Efectividad alTratamiento
.
Ninguna píldora puede ayudarme a lidiar con el problema de no querer tomarlas Godwin and Jamison, 90
El punto más difícil no es que respondan al tratamiento;
sino que continúen tomando la medicación Lieberman, 90
EPS + TDEPS + TD
Weight Gain
Weight Gain
Insulin Resistance
Insulin Resistance
Hyper-glycemiaHyper-
glycemia
CVDCVD
Hyper-lipidemiaHyper-
lipidemia
Weight GainWeight Gain
DiabetesDiabetes
Hyper Glycemia
Hyper Glycemia
Insulin Resistance
Insulin Resistance
QTcQTc
CVDCVD
DyslipidemiaDyslipidemia
Prior Safety Concerns Current Safety Concerns
SHIFT IN RISK PERCEPTION
QTc
EPS
Neurologic Side Effects
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
THE CONTINUUM OF CARE
EfficacyEfficacyEfficacyEfficacy
SafetySafetySafetySafety
1-3 days 7-14 days 6+ months
ControlBehavior
(agitation)
Negative symptom reliefImprove mood and
depressive symptomsCognitive improvement
Relapse Prevention
Positive symptom reliefHostility, aggressionSmooth IM to PO transitionAlleviation of comorbid
depressive/manic symptoms
Acute dystoniaSedationOrthostasisQTc prolongation
EPSDrug-drug interactionsQTc prolongation
TDHyperprolactinemiaWeight gainHyperglycemiaQTc prolongation
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
occupazione recettoriale efficacia antipsicotica 60-70%
iperprolattinemia > 70% EPS > 80%
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%
L’efficacia clinica degli APT è inevitabilmente associata all’iperprolattinemia
L’aumento della prolattina è un marker della azione dei farmaci APT
X
MOVIMIENTOS ANORMALES POR AP:
BUTIROFENONAS
SULPIRIDA
AMISULPRIDE
RISPERIDONA
PROMAZINICOS
ARIPRIPAZOL
OLANZAPINA
ZIPRASIDONA
CLOZAPINA
QUETIAPINALopez 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
Lower tardive dyskinesia risk
Fewer motor side effects
Less dysphoria
Cognitive advantage
Negative symptoms
benefit
EPSAdvantage
Improvedcompliance
Jibson and Tandon 1998
Quetiapine was better tolerated than haloperidol in terms of EPS as demonstrated by the significant differences in the Simpson Scale
and Abnormal Involuntary Movement Scale scores (P<0·05). Although patients in both groups had elevated serum prolactin
concentrations at baseline, mean serum prolactin concentration decreased (by 16·5 [mu]g/l) in quetiapine-treated patients, yet increased (by 5·9 [mu]g/l) in patients treated with haloperidol.
Conclusion. Quetiapine is an effective and well tolerated antipsychotic of comparable efficacy to haloperidol and lacks the
latter compound's effect on prolactin and EPS.
D. L. COPOLOV, C. G. G. LINK and B. KOWALCYK. Mental Health Research Institute of Victoria, Australia: AstraZeneca Psychological Medicine (2000), 30: 95-
105 Cambridge University Press
QUETIAPINE VS HALOPERIDOL
PNIE DEL TRATAMIENTO DE 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
AUMENTO PROLACTINA POR AP:
BUTIROFENONAS
SULPIRIDA
AMISULPRIDE
RISPERIDONA
PROMAZINICOS
ZIPRASIDONA
ARIPRIPAZOL OLANZAPINA QUETIAPINA
CLOZAPINALopez Mato A., 2003
HYPERPROLACTINEMIA
Amenorrhoea
GalactorrhoeaBreast
enlargement
Impotence
Gynaecomastia
Prolactin elevation
Sexual dysfunction
Osteoporosis
Data from Arvanitis et al 1997
LA PROLACTINA ES MAS QUEUNA HORMONA DE MATERNAJE
• Función en “coping” (afrontamiento) al stress• Función metabólica (hormona anaerobia)• Función sobre SNC (crecimiento neuronal y sinaptogénesis)• Función sobre inmunomodulación• Función sobre conductas sexual y maternal
Illa G en Lopez Mato A y col, 2002 Psiconeuroinmunoendocrinologia.
Aspectos epistemológicos, clínicos y terapéuticos
PROLACTIN IN UNMEDICATED SCHIZOPHRENIC
PRL levels are not elevated in un medicated schizophrenic patients
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 normalrange may be correlated to different subgroups of disease
PRL IN SCHIZOPHRENIA SUBTYPES
M
M
F
F
The “normal” range of serum prolactin levels
seems to obscure significant differences
between specificgroups of schizophrenia
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
Seroquel (mg/day)
Data from Arvanitis et al 1997
Placebo 75 150 300 600 750 Haloperidol12 mg/day
**p<0.01 vs placebo
Mean change in prolactinlevels (µg/L) frombaselineat endpoint
QUETIAPINE AND PROLACTIN
5
0
-5
20
15
10
**
NORMALISATION OF PREVIOUSLY ELEVATED PROLACTIN LEVELS
-10
-5
0
5
10
15LSM change in prolactin levels (µg/L) from baseline to end of treatment
Data on file - AstraZeneca
Seroquelup to 800 mg/day
(n=429)
Haloperidolup to 20 mg/day(n=320)
***
***p<0.001 vs haloperidolMeta-analysis of 3 double-blind, randomised trials
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 CANCER
In mice deficient for PRL or for its receptor (knockout models),the appearance and/or the development
of virus-induced mammary or prostate tumors was delayed, or even inhibited
- Vomachka AJ, et al. 2000 Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth. Oncogene 19:1077-1084
- Robertson FG, et al. 2003 Prostate development and carcinogenesis in prolactin receptor knockout mice. Endocrinology 144:3196-3205
PRL may exert a permissive role in tumor growth
PRL AND BREAST CANCERTwo 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 rangehad 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 Currently we don’t know whether hyperprolactinemic patientshyperprolactinemic patients are at are at high risk of developing cancers (no large scale studies)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 CANCEROne 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 there is no correlation between PRL levels and the risk to develop
prostate cancerprostate 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 no correlation between hyperprolactinemia and prostate hyperplasia
was foundwas 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
PNIE DEL TRATAMIENTO DE 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
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
HIPOTIROIDISMO
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. Routine monitoring of thyroid function in patients
without history of thyroid disease is not recommended. 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 volunteersAlexandro de Borja Gonçalves Guerra, Saulo Castel
The International Journal of Neuropsychopharmacology (2005), 8: 49-57
Although not reported with Quetiapine, disruption of the body’s ability to reduce core body temperature has been
attributed to antipsychotic agents. Appropriate care is advised when prescribing Quetiapine
for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic
activity, or being subject to dehydration.
De Seroquel
BODY TEMPERATURE REGULATION:
PNIE DEL TRATAMIENTO DE 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
CLINICA DIARIAAUMENTO 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
• Personalidad narcisística
• 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
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
Antagonismo Receptores H1 y 5-HT2c
Acción en Hipotálamo lateral y ventromedial
MECANISMOS INVOLUCRADOS EN EL AUMENTO
DE PESO
Reducción en el Metabolismo
Basal
Insulinoresistencia
Reducción de Acatisia
Liberación de TNF-y otras Citoquinas
Cambios en la Sensibilidad a
la Leptina
PESO Y DOSIS
-2
-1
0
1
2
3
4
5
300 mg >300-500 mg >500 mg
Mean duration of treatment (days)
343 407 327
(n=103) (n=94) (n=174)
Change in mean weight from baseline (kg)
Brecher et al 2000
PESO Y TTO CRONICO
53 weeks Dose up to 800 mg/day(n=112)aFavourable increase or decrease Data on file - AstraZeneca
0
10
20
30
40
50
60
70
80
Shift in BMI category from baseline
Patients (%)
Unfavourabledecrease
Favourableshifta
Unchanged Unfavourableincrease
0
10
20
30
40
50
60
70
80
Data on file - AstraZeneca
TTO CRONICO Y OBESIDAD SEVERA
Shift in BMI category from baseline
Unfavourabledecrease
Favourabledecrease
Unchanged Unfavourableincrease
53 weeks(n=20)Dose up to 800 mg/day
Patients(%)
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 - cardíaco• Desórdenes hematológicos e inmunes• Desórdenes de la sexualidad• Teratogénesis, carcinogénesis y otros
•
Lopez Mato. 2002
LABORATORY ASSESSMENTSLABORATORY ASSESSMENTSLABORATORY ASSESSMENTSLABORATORY ASSESSMENTS
Mean Change From Baseline (SD)
PBO (n=118)
Seroquel XR
Seroquel IR 400
mg(n=123)
400 mg(n=113)
600 mg (n=113)
800 mg(n=121)
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)
Insulin (pmol/L) 0.48 (93.92)21.99 (127.41)2.14
(106.29)7.39
(97.70)31.69
(139.53)Total cholesterol (mmol/L)
-0.15 (0.80) 0.17 (0.85) 0.25 (0.93) 0.17 (0.85) 0.36 (0.82)
LDL cholesterol (mmol/L)
-0.10 (0.66) 0.07 (0.67) 0.22 (0.74) 0.04 (0.76) 0.25 (0.66)
HDL cholesterol (mmol/L)
-0.01 (0.24) 0.01 (0.23) -0.02 (0.26) -0.01 (0.25) 0 (0.28)
Triglycerides (mmol/L) -0.11 (0.78) 0.17 (0.92) 0.15 (1.12) 0.31 (1.11) 0.32 (0.85)
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 - cardíaco• Desórdenes hematológicos e inmunes• Desórdenes de la sexualidad• Teratogénesis, carcinogénesis y otros
•
Lopez Mato. 2002
CHOLESTEROL AND CHOLESTEROL AND TRIGLYCERIDE ELEVATIONS: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.
PNIE DEL TRATAMIENTO DE 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 - cardíaco• Desórdenes hematológicos e inmunes• Desórdenes de la sexualidad• Teratogénesis, carcinogénesis y otros
•
Lopez Mato. 2002
CLINICA DIARIA RIESGO DE SIADH POR AP:
PROMAZINICOS
ZIPRASIDONA
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 Challenging Case of Syndrome of Inappropriate Secretion of Antidiuretic Hormone in an Elderly Patient Secondary to Quetiapine. Southern Medical Journal. 100(8):832-833, August 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, vol. 150, no35, pp. 1944-1948
PNIE DEL TRATAMIENTO DE 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 - cardíaco• Desórdenes hematológicos e inmunes• Desórdenes de la sexualidad• Teratogénesis, carcinogénesis y otros
•
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
serum transaminases (primarily ALT) have been reported.
- 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.
These hepatic enzyme elevations usually occurred within
the first 3 weeks of drug treatment and promptly returned
to pre-study levels with ongoing treatment with Quetiapine.De Seroquel
RIESGO DE EVENTOS CARDIOLOGICOS POR AP:
TIORIDAZINA
ZIPRASIDONA
SERTINDOL
PROMAZINICOS
QUETIAPINA
Lopez Mato A., 2003
-5
0
5
10
15
20
25
30
35
40
Ziprasidone160 mg
Risperidone16 mg
Olanzapine20 mg
Seroquel750 mg
Thioridazine300 mg
Haloperidol15 mg
(n=24) (n=25) (n=27) (n=27) (n=31) (n=30)
AA Y QT
Mean QTcchange from baselinea (msec)
aPfizer study 54 baseline correctionDoses are highest total daily doses evaluated
Pfizer Study 54, FDA Psychopharmacological Drug Advisory Committee 19th July 2000
Seroquel causes an increase in heart rate (HR) and a shortening of QT interval
No dose-related increase in QT interval (corrected for HR) with Seroquel
No potentially clinically significant outliers (QTc >60 msec change from baseline, QTc >500 ms)
QUETIAPIN AND CARDIAC REPOLARISATION (QT INTERVAL)
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
- 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/fluoxetineAtypical antipsychotics used to treat dementia-related psychosis carry an “increased risk of death compared with placebo” FDA Warning on Mortality. April 11, 2005
NEW WARNING
PNIE DEL TRATAMIENTO DE 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
RIESGO DE EVENTOS HEMATOLOGICOS POR AP
CLOZAPINA
PROMAZINICOS
CARBAMACEPINA
LITIO
Lopez Mato A., 2003
NEUTROPHIL COUNTSNEUTROPHIL COUNTS
Neutrophil Count*
PBO (n=118)
Seroquel XR
Seroquel IR 400
mg(n=123)
400 mg(n=113)
600 mg (n=113)
800 mg(n=121)
<0.5 x 109 cells/L, na
0 0 0 1† 0
<1.5 x 109 cells/L, na
0 2 0 3 3
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
PNIE DEL TRATAMIENTO DE 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
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 inducepriapism, and it is possible that Quetiapine may share this capacity.
PNIE DEL TRATAMIENTO DE 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
FDA - RIESGO DE EVENTOS TERATOGENICOS POR AP:
ANTICOLINERGICOS C
BUTIROFENONAS C
PROMAZINICOS C
ARIPRIPAZOL C
ZIPRASIDONA C
RISPERIDONA C
QUETIAPINA C
OLANZAPINA CB
CLOZAPINA B Lopez Mato. 03
ANTIPSYCHOTICS IN POSTPARTUM
• Prolactin-sparing antipsychotic may be useful, e.g., olanzapine and quetiapine.
• Clozapine use is restricted because of the haematological risk.
• The risk of relapse of schizophrenia during this time is also significant like the mood disorders
Dr. Ahmed Shoka
CATARATAS• 26% of schizophrenics have lens opacities
– multiple cataractogenic risk factors
• 620,000 Seroquel exposures through May 31 2000
• 32 cases of lens opacities reported
• Most had concomitant risk factors: trauma, hypertension, diabetes, known cataractogens
• Independent evaluation by ophthalmologist consultant did not identify hallmarks suggesting lens toxicity attributable to Seroquel
McCarty et al 1999; Laties et al 2000
PNIE DEL TRATAMIENTO DE 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
SEROQUEL ES SEGURIDAD Incidence of EPS no different to placebo across the full dose range
Significantly less EPS than haloperidol, even at higher doses
Incidence of EPS does not increase with long-term use
Low risk of tardive dyskinesia
Low level of sexual dysfunction (prolactin levels equivalent to placebo across all doses)
Significantly lower prolactin levels than standard antipsychotics
Weight neutral in long-term monotherapy
No clinically significant effect on QT interval - ECG monitoring not require
No requirement for blood or thyroid or liver monitoringMeats 1997; Data on file - AstraZeneca