QUETIAPINA Perfil Psiconeuroinmunoendócrino ANDREA MARQUEZ LOPEZ MATO PABLO BERETTA Instituto de Psiquiatría Biológica Integral

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

Maudsley Hospital Prescribing Guidelines

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


• 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


•

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.



•

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



•

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



•

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



•

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.



•

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

RIESGO DE EVENTOS OFTALMOLOGICOS POR AP:

QUETIAPINA ????PROMAZINICOS

Lopez Mato A., 2003

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



•

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

SEROQUEL ES SEGURIDAD

MUCHAS GRACIAS

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QUETIAPINA Perfil Psiconeuroinmunoendócrino ANDREA MARQUEZ LOPEZ MATO PABLO BERETTA Instituto de Psiquiatría Biológica Integral