QUETIAPINA Perfil Psiconeuroinmunoendócrino ANDREA MARQUEZ LOPEZ MATO PABLO BERETTA Instituto de Psiquiatría Biológica Integral www.ipbi.com.ar

RECEPTOR BINDING Goldstein 1999 Clozapine Seroquel Haloperidol 5HT2A 5HT1A A2 H1 M Clozapine A1 D1 D2 5HT2A 5HT1A A1 A2 H1 Seroquel Receptor A1, 2 = a1, a2 adrenergic D1,2 = dopamine H1 = histamine 5HT1A, 2A = serotonin M = muscarinic D1 D2 5HT1A A1 Haloperidol H1 D1 D2 5HT2A A1 H1 M Olanzapine D2 5HT2A A1 A2 H1 Risperidone D1 Seroquel – receptor binding characteristic of an atypical antipsychotic Seroquel interacts with a broad range of neurotransmitter receptors and this may be responsible for its atypical antipsychotic properties1 Atypical antipsychotics, like Seroquel, clozapine, risperidone and olanzapine, have a higher 5HT2A relative to D2 binding ratio1 By contrast, the standard antipsychotic, haloperidol, has a narrower range of receptor affinities and a higher D2 relative to 5HT2A binding ratio1 Not shown here are binding characteristics to D3 receptors. Seroquel and clozapine have similar binding to D3 receptors2 References 1. Goldstein JM. Emerging Drugs 1999; 4: 127-151. 2. Goldstein JM. In: Holliday SG, Ancill RJ, MacEwan GW, eds. Schizophrenia: Breaking Down the Barriers. John Wiley & Sons Ltd, 1996: 177-236.

Tolerabilidad Seguridad El punto más difícil no es que respondan al tratamiento; sino que continúen tomando la medicación Lieberman, 90 Eficacia Tolerabilidad Seguridad Adherencia/ Continuidad Efectividad al Tratamiento 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 Resistance Weight Gain Insulin Resistance Hyper- lipidemia EPS QTc Dyslipidemia CVD QTc Hyper- glycemia

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

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

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

X 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 Parkinsonismo Cognitivo EPS Distonía Diskinesia tardía Parkinsonismo Cognitivo Pensamiento enlentecido y pobre Sentimiento de vacío Dificultades de concentración Gerlach 98

PARKINSONISMO Parkinsonismo Social Parkinsonismo Emocional 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 EPS Advantage Improved compliance Negative Lower tardive dyskinesia risk Fewer motor side effects Less dysphoria Cognitive advantage Negative symptoms benefit EPS Advantage Improved compliance Low EPS risk – the essence of atypicality As an atypical antipsychotic, Seroquel is characterised by being at least as effective as standard antipsychotics with a much lower risk of extrapyramidal symptoms (EPS) This relative lack of EPS with atypical antipsychotics may have a favourable effect on cognition, compliance and patients’ subjective experience of treatment Reference: Jibson MD and Tandon R. J Psychiatr Res 1998; 32:215-228. Jibson and Tandon 1998

QUETIAPINE VS HALOPERIDOL 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

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 CLOZAPINA Lopez Mato A., 2003

HYPERPROLACTINEMIA Prolactin elevation Sexual dysfunction Gynaecomastia Amenorrhoea Prolactin elevation Impotence Osteoporosis Breast enlargement Galactorrhoea Data from Arvanitis et al 1997

LA PROLACTINA ES MAS QUE UNA 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

PRL levels are not elevated in un medicated schizophrenic patients 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 normal range may be correlated to different subgroups of disease

serum prolactin levels seems to obscure significant differences PRL IN SCHIZOPHRENIA SUBTYPES F M The “normal” range of serum prolactin levels seems to obscure significant differences between specific groups of schizophrenia patients F M 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 Mean change in prolactin levels (µg/L) from baseline at endpoint 20 ** 15 10 5 -5 Placebo 75 150 300 600 750 Haloperidol 12 mg/day Seroquel (mg/day) **p<0.01 vs placebo Data from Arvanitis et al 1997

Haloperidol up to 20 mg/day NORMALISATION OF PREVIOUSLY ELEVATED PROLACTIN LEVELS Seroquel up to 800 mg/day (n=429) Haloperidol up to 20 mg/day (n=320) LSM change in prolactin levels (µg/L) from baseline to end of treatment Seroquel allows normalisation of previously elevated prolactin levels This is a meta-analysis1 from three double-blind studies (6-week2,3 and 8-week, in partial responders4) in which patients with schizophrenia received Seroquel (up to 800 mg/day; n=429) or haloperidol (up to 20 mg/day; n=320). These data are from a last value carried forward analysis References 1. Data on file – AstraZeneca. 2. Arvanitis LA et al. Biol Psychiatry 1997; 42: 233-246. 3. Copolov DL et al. Psychol Med 2000; 30: 95-105. 4. Emsley RA et al. Int Clin Psychopharmacol 2000; 15: 121-131. *** 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 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 PRL may exert a permissive role in tumor growth - 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 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

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 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.

ACTH secretion showed no difference compared to placebo. 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

BODY TEMPERATURE REGULATION: 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

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 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 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

Reducción en el Metabolismo Basal PESO Y AA Liberación de TNF- y otras Citoquinas Reducción en el Metabolismo Basal Acción en Hipotálamo lateral y ventromedial Reducción de Acatisia Antagonismo Receptores H1 y 5-HT2c MECANISMOS INVOLUCRADOS EN EL AUMENTO DE PESO Insulinoresistencia Cambios en la 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 mean weight from baseline (kg) £300 mg 343 407 327 Mean duration of treatment (days) (n=103) (n=94) (n=174) Brecher et al 2000

Shift in BMI category from baseline PESO Y TTO CRONICO Patients (%) 80 70 60 50 40 30 20 10 Favourable shifta Unfavourable decrease Unchanged Unfavourable increase 53 weeks Dose up to 800 mg/day (n=112) aFavourable increase or decrease Shift in BMI category from baseline Data on file - AstraZeneca

Shift in BMI category from baseline TTO CRONICO Y OBESIDAD SEVERA Patients (%) 80 70 60 50 40 30 20 10 Unfavourable decrease Favourable decrease Unchanged Unfavourable increase 53 weeks (n=20) Dose up to 800 mg/day Shift in BMI category from baseline Data on file - AstraZeneca

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 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) 0.36 (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 (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 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

AA Y QT Mean QTc change from baselinea (msec) aPfizer study 54 baseline correction Doses are highest total daily doses evaluated Mean QTc change from baselinea (msec) 40 35 30 25 20 15 10 5 Effect of antipsychotic drugs on QTc (steady state) The Pfizer Study 541 compared the effects of antipsychotic drugs using 7 formulae including a Baseline heart rate correction formula. This approach was recommended by the FDA in preference to using a ‘standard’ heart rate correction formula such as Bazett’s or Fridericia. The FDA recommended calculating a dataset-specific heart rate correction formula for each drug’s baseline dataset. This Baseline heart rate correction formula was, by definition, the best correction formula for the ‘baseline’ QT interval and heart rate data. The Baseline heart rate correction formula appropriate for each drug’s dataset was then applied to the QT intervals during drug treatment. This approach ensures a meaningful comparison across all drugs in spite of their differing effects on heart rates1 Antipsychotics were evaluated over the following dose ranges: ziprasidone (20-80 mg twice-daily); risperidone (1-8 mg twice-daily); olanzapine (5-20 mg once-daily); Seroquel (25-375 mg twice-daily), thioridazine (25-150 mg twice-daily) and haloperidol (2-15 mg once-daily) Thioridazine has received a black box warning in the US for risk of sudden death related to its effects on cardiac repolarisation (QT interval). The warning states that a Pfizer study found that "the mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine,and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine".2 Although Seroquel was clearly associated with a decrease in QT interval across a wide plasma concentration range, the effects of Seroquel, risperidone and olanzapine on QTc interval appear to be indistinguishable from each other. The effect of haloperidol on the QTc interval is considered to be equal to that of placebo1 Reference 1. FDA Background on Zeldox TM (ziprasidone hydrochloride capsules) Pfizer, Inc. Psychopharmacological Drugs Advisory Committee 19 July 2000. Advisory Committee Briefing Document http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf 2. NDA 20-825 Approval letter and labeling http://www.fda.gov/cder/foi/label/2001/20825lbl.pdf -5 Olanzapine 20 mg Risperidone 16 mg Seroquel 750 mg Haloperidol 15 mg Ziprasidone 160 mg Thioridazine 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

QUETIAPIN AND CARDIAC REPOLARISATION (QT INTERVAL) 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) Seroquel – no clinically significant effect on cardiac repolarisation (QT interval) Bazett’s heart rate correction formula has been conclusively shown to overestimate the effects on cardiac repolarisation (QTc interval) when heart rates are increased1,2 The conclusions presented in the slide are based on data that were considered by the European regulatory authorities3 and the FDA during the approval process of Seroquel and in the FDA review of Pfizer Study 054 In addition, these data are now independently confirmed by the Pfizer study 54, which was conducted at the FDA’s request.4 In this study, the effect of Seroquel on the QT interval was examined across a 2 order of magnitude range of plasma concentration in the presence of a potent CYP 450 3A4 metabolic inhibitor. The absence of a dose- (or concentration-) related effect on QTc interval was confirmed for Seroquel. Of the antipsychotic drugs assessed, Seroquel was the only antipsychotic that demonstrated such a clear shortening of the QT interval and no prolongation of the QT interval (appropriately corrected) across a wide plasma concentration range4 The plasma concentration extended over a 2 order of magnitude range (102 to 104 ng/ml) References 1. Karjalainen J et al. J Am Coll Cardiol 1994; 23: 1547-1553. 2. Funck-Bentano C and Jaillon P. Am J Cardiol 1993; 72: 17B-22B. 3. Mutual Recognition Procedure No. NL/H/156/01-03, Reference Member State: The Netherlands, Assessment report for Seroquel (film-coated tablets containing quetiapine fumarate) August 1999. 4. FDA Background on Zeldox TM (ziprasidone hydrochloride capsules) Pfizer, Inc. Psychopharmacological Drugs Advisory Committee 19 July 2000. Overview Memo by Thomas Laughren, M.D.; Cardio Review, Maryann Gordon, M.D. http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1b.pdf 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

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 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 1† <1.5 x 109 cells/L, na 2 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 induce priapism, 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

OFTALMOLOGICOS POR AP: 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 Lens Opacities - safety update 26% of schizophrenic patients exposed to psychotropic medication from a community mental health service had lens opacities1 Of 620,000 patients in the US (cases reported between September 1997 and 31 July 2000) treated with Seroquel, lens opacities have developed in only 32 patients. These 32 reported cases are a global composite, making the reporting rate even less2. The mean age of these cases was 42.6 years; male:female ratio was 1:1.2. Most of the reported cases had risk factors for lens opacities and some cases had cataracts at baseline2 No conclusive evidence of direct linkage between Seroquel and ocular changes has been found2 References 1. McCarty CA et al. Ophthalmology 1999; 106: 4 683-7. 2. Laties AM et al. Poster presented at the American College of Neuropsychopharmacology Annual Meeting, Puerto Rico, 2000. 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 monitoring Seroquel - tolerability in schizophrenia Summary slide Meats 1997; Data on file - AstraZeneca

ANDREA LOPEZ MATO PABLO BERETTA MUCHAS GRACIAS SEROQUEL ES SEGURIDAD ANDREA LOPEZ MATO PABLO BERETTA www.ipbi.com.ar