Atypical antipsychotics and the metabolic syndrome. Thomas R. Dekoj, MS3 UIC College of Medicine

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1 Atypical antipsychotics and the metabolic syndrome Thomas R. Dekoj, MS3 UIC College of Medicine

2 Antipsychotic uses Schizophrenia and related d/o ~1% Bipolar ~2% used widely in schizophrenia spectrum d/o, bipolar d/o, dementia, psychotic depression, autism, developmental d/o also used in delirium, aggressive behavior, personality d/o, PTSD

dementia, psychotic depression, autism, developmental d/o

3 Metabolic Syndrome: Defined ATP-III Three or more of the following in adults: Obesity (waist circumference) Elevated triglycerides (>150) Hypertension Elevated fasting glucose ~25% of U.S. adults qualify ~50% of schizophrenics may qualify WHO Two or more of the following in adults: Obesity (BMI, waist:hip) Elevated triglycerides (>150 or HDL) Hypertension (>160/>90) Elevated fasting glucose (>110) Microalbuminemia (AER>20) ICD , dysmetabolic syndrome X

adults qualify ~50% of schizophrenics may qualify WHO Two or more of the following in adults: Obesity (BMI,

4 Cause and effect Hyperinsulinemia/insulin resistance/hyperphagia WEIGHT GAIN Hyperglycemia Excess body weight c abdominal adiposity Hypertension Dyslipidemia DM II CVD Obesity hypercoagulable states, endothelial dysfunction, polycystic ovarian disease Morbidity and mortality: CVA, MI, etc.

Dyslipidemia DM II CVD Obesity hypercoagulable states, endothelial

5 Increased risk in Psychiatric population Without treatment, increased prevalence of diabetes mellitus II * : schizoaffective (50%) bipolar I (26%) MD (18%) dementia(18%) schizophrenia(13%) (BMI concordance) FDA request for SE label in 2003: Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Presence of schizophrenia increased the mortality of MI by 34% (Druss) * Regenold et al.

use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and

6 Antipsychotics and Side Effects Typicals: antagonism haloperidol fluphenazine trifluoperizine thiothixine perphenazine pimozide molindone loxapine chlorpromazine thioridazine mesoridazine dopamine High level EPS Low level EPS Atypicals: olanzapine clozapine risperidone quetiapine ziprasidone aripiprazole dopamine & serotonin weight gain no weight gain

thioridazine mesoridazine dopamine High level EPS Low level EPS Atypicals: olanzapine

7 Atypical antipsychotics and Metabolic Syndrome I Weight gain Olanzapine Risperidone Quetiapine 27 lbs in the 1 st year (Nemeroff) 16 lbs in 6 mos. (Zuddas) 15.1 lbs in 1 st year (Findling) Diabetes mellitus II: up to 36% of patient on clozapine may develop DMII after 60 months (Henderson et al.) These findings are present in other atypicals as well at similar profile as the tendency toward weight gain Dyslipidemia: There appears to be varying effects of atypicals on cholesterol, but the effects on TG are depicted: Ziprasidone Risperidone Olanzapine Quetiapine Thioridazine Haloperidol Median % Chg -28% -6.7% 31% 18.3% 7.9% -18% (FDA) DKA There is increased evidence that treatment with atypical antipsychotics is associated with an increased incidence of New-onset diabetes mellitus and DKA (Wilson)

8 Atyp anti-ψ and Met. Synd. II list of studies In pediatric pts, treatment caused significant (>7%) weight gain olanzapine 90% n=21 risperidone 42.9% n=21 haloperidol 12.5% n=8 previous neuroleptic hx, dosage, response, illness duration not correlated with weight gain (Ratzoni, Gothelf) Over one year, in pts with autism and MR, Weight gain occurred. (Hellings, Zarcone) 8-12 y/o 8.2 kg kg kg Retrospective, adult pts with MR reported weight gain over two years in 37/39 pts on average of 8.3 kg. Calorie restriction did not lead to weight loss and weight gain and dose are unrelated. (Cohen, Glazewski) In 63 pediatric pts with autism, tx with risperidone increase in weight 5 kg in 6 mo. (corrected for age and gender standards), but that the degree is not correlated with serum leptin levels. (Martin, Scahill, Anderson) In 60 adolescents, over 6 mo. there was an average increase in BMI of 3.67 when tx with ripseridone. There was significant difference between ripseridone and the typicals and there was no correlation with dose and BMI increase. (Kelly, Conley, Love) A retrospective study on 636 adults showed a >7% weight increase in patients tx with antipsychotics (Bobes, Rejas, Garcia-Garcia) olanzapine 45.7% risperidone 36.6% haloperidol 22.4%

(Hellings, Zarcone) 8-12 y/o 8.2 kg 13-16 8.4 kg 21-21 5.4 kg Retrospective, adult pts with MR reported weight gain over two years in 37/39 pts on average of 8.3 kg.

9 Antipsychotics and the metabolic syndrome olanzapine clozapine weight gain risperidone quetiapine ziprasidone aripiprazole no weight gain increases in fasting glucose and lipid levels for patients unlinked to weight parameters clozapine olanzapine risperidone weight gain worsening lipid profile + + D risk for diabetes + + D quetiapine aripirazole ziprasidone ++ +/- +/- D - - D - -

unlinked to weight parameters clozapine olanzapine risperidone weight gain +++ +++ ++ worsening

10 Specific concerns/risks in pediatric patients Short-term effects medical physical development, future risks psychological emotional effects?????? psychiatric noncompliance Unknown long-term effects medical CVD, DMII, etc. psychological resentment for disease and meds psychiatric noncompliance

????? psychiatric noncompliance Unknown long-term effects medical CVD,

11 Practice guidelines and screening -Consideration of risks at prescription -Patient/family education about DKA, hyperglycemia and metabolic syndrome -Baseline and follow-up: baseline 4wk 8wk 12 wk quartrly yearly 5yr History X X Weight (BMI) X X X X X Waist X X Blood Pressure X X X Fast glucose X X X Fasting lipid X X X -Referral to specialized services as needed consider medical management -Continued re-evaluation and medications changes at onset of decreasing likelihood of favorable long-term risk:benefit ratio

X Blood Pressure X X X Fast glucose X X X Fasting lipid X X X -Referral to specialized services as needed consider medical

12 Conclusions -Long-term therapy must be assumed in many cases -Medication choice is critical -Benefit to risk ratio -Perhaps metabolic syndrome and psychosis can be further linked in an effort to elucidate their causes and find more effective treatment for both disorders Estimations about clozapine to ponder: 492/100,000 patients will be saved from suicide with antipsychotics 416/100,000 will die of the increased risk of CVD (based on Framingham heart study due to weight gain alone)

effective treatment for both disorders Estimations about clozapine to ponder: 492/100,000 patients will be saved from

13 references -Consensus development conference on antipsychotic drugs and obesity and diabetes. J Clin Psychiatry Feb;65(2): (PMID ) -Casey, Haupt, Newcomer, Henderson, et al.: Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry. 2004;65 Suppl 7:4-18 ( ) -Martin, Scahill, Anderson, Aman et al.: Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry Jun;161(6): (PMID ) -McConville, Sorter: Treatment challenges and safety considerations for antipsychotic use in children and adolescents with psychoses. J Clin Psychiatry. 2004;65 Suppl 6:20-9 -Stigler, Potenza, Posey, McDougle: Weight gain associated with atypical antipsychotic use in children and adolescents: prevalence, clinical relevance, and management. Paediatr Drugs. 2004;6(1):33-44 (PMID ) -Gothelf, Apter, Reidman, et al.: Olanzapine, risperidone and haloperidol in the treatment of adolescent patients with schizophrenia. J Neural Transm May;110(5): (PMID ) -Pavuluri, Janicak: Psychopharmacotherapy at your fingertips for children adolescents and adults. UIC Publication Services, Chicago, Regenold, Thapar, Marano, et al: Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and schizoaffective do independent of psychotropic drug use J Affect Disord Feb;73(3): (PMID ) -Robes, Rejas, Garcia-Garcia et al.: Weight gain in patients with schizophrenia treated with risperidone, olanzapine, quetiapine or haloperidol: results of the EIRE study Schizophr Res Jul 1;62(1-2):77-88 (PMID ) -Wilson, D'Souza, Sarkar, Newton, Hammond: New-onset diabetes and ketoacidosis with atypical antipsychotics Schizophr Res Jan 1;59(1):1-6. (PMID ) -Meyer, JM: A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry May;63(5): ( ) -Ratzoni, Gothelf, Brand-Gothelf et al.: Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study J Am Acad Child Adolesc Psychiatry Mar;41(3): (PMID ) -Cohen, Glazewski, Khan, Khan: Weight gain with risperidone among patients with mental retardation: effect of calorie restriction. J Clin Psychiatry Feb;62(2):114-6 (PMID ) -Hellings, Zarcone, Crandall, Wallace, Schroeder: Weight gain in a controlled study of risperidone in children, adolescents and adults with mental retardation and autism J Child Adolesc Psychopharmacol Fall;11(3): (PMID ) FDA Psychopharm Drugs Advisory Committee. Briefing document for Zeldox capsules, July 19, Findling, McNamara, Gracious: Paediatric uses of atypical antipsychotics. Expert Opin Pharmacother Jul;1(5): ( ) -Henderson, Cagliero, Gray, et al.: Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry Jun;157(6): (PMID ) -Zuddas, DiMartino, Muglia, et al.: Long-term risperidone for pervasive developmental disorder: efficacy, tolerability, and discontinuation. J Child Adolesc Psychopharmacol Summer;10(2):79-90 (PMID ) -Kelly, Conley, Love, Horn, Uschchak: Weight gain in adolescents treated with risperidone and conventional antipsychotics over six months Child Adolesc Psychopharmacol. 1998;8(3):151-9 (PMID ) -Nemeroff: Dosing the antipsychotic medication olanzapine. J Clin Psychiatry. 1997;58 Suppl 10:45-9 (PMID )

2004;65 Suppl 7:4-18 (15151456) -Martin, Scahill, Anderson, Aman et al.: Weight and leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am J Psychiatry.

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