Psychotropic Drug Induced Metabolic Disorders

DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 APRIL 2007 Review Article Psychotropic Drug Induced Metabolic Disorders J.K. Trivedi, Kumar Gaurav Department of Psychiatry, K.G. Medical University, Lucknow-226003 Abstract According to a report from the Centers for Disease Control and Prevention released in April, the leading cause of death contibuting to that shortened lifespan is not the patients mental illness, but rather something largely preventable cardiovascular disease. Metabolic disorders are known complications of newer antipsychotics. The term Metabolic Syndrome refers to a syndrome consisting of central obesity as indicated by excessive visceral fat, plasma lipid abnormalities, glucose dysregulation, and high blood pressure. The metabolic syndrome develops gradually, different drugs have differential propensity to cause it. This is a dreadful condition as it induces medical morbidities, which may be life threatening in patients. The criteria for diagnosing the metabolic syndrome propsed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used but are not universally accepted. Common manifestations are dyslipidemia, hypertension, weight gain, increase in blood glucose etc. This review covers the latest available information on the drug induced metabolic syndrome. Risk factors and mechanisms are discussed. Introduction Patients with schizophrenia and bipolar disorder lose as much as 20 years off their average life expectancy compared with similar individuals in the general population without serious mental illness. According to a report from the Centers for Disease Control and Prevention released in April, the leading cause of death contibuting to that shortened lifespan is not the patients mental illness, but rather something largely preventable cardiovascular disease. These statistics and others were cited by an expert panel as indirect evidence that the filed of psychiatry is earning a failing grade when it comes to managing comorbidity in patients with schizophrenia and bipolar disorder especially those patients who are taking second generation antipsychotics (SGAs). This class of drugs is generally considered to be linked closely with increased risk of metabolic syndrome, a leading risk factor for cardiovascular disease. 1-5 Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation is patients treated with secondgeneration (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and tr eatment with these medications. 5-6 Second generation antipsychotics (SGA) have demonstrated sever al advantages over first generation antipsychotics (FGA) in terms of positive, negative, cognitive, and affective symptoms and a lower propensity for extrapyramidal side effects. Despite these undeniable advantages, SGA have been associated with causing and exacerbating metablic disorders, such as obesity, diabetes, and hyperlipidemia. 7 Substantial evidence from a variety of human populations, including some recent confirmatory 32 Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society

APRIL 2007 DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. 8-10 What is Metabolic Syndrome? The term Metabolic Syndrome refers to a syndrome consisting of central obesity as indicated by excessive visceral fat, plasma lipid abnormalities, glucose dysregulation, and high blood pressure. The criteria for diagnosing the metabolic syndrome propsed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most current and widely used but are not universally accepted. NCEP ATP III/WHO defines metabolic syndrome as: Obesity: High waist circumference BMI > 30 Dyslipidemia Hypertension High fasting glucose (> 110mg/dL) Expert panel on detection, evaluation and treatment of high blood cholesterol recommends the usage of the term metabolic syndrome if any three of the following five criteria are fulfilled. Obesity (Waist > 40 in men and 35 in women) High density lipoprotein cholesterol < 40 mg/ dl in men and < 50 mg/dl in women Triglycerides > = 150 mg/dl Blood pressure > 130 mm Hg systolic or 85 mmhg diastolic Fasting blood glucose >= 110 mg/dl A Prothombotic State with Elevated plasminogen activator inhibitor -1(PAI-1) AND A Proinflammatory State with increased C-reactive protein (CRP) are other features of metabolic syndrome. The metabolic syndrome has become increasingly common in the United States and other developed countries due to diet and limited exercise. It is estimated that about 20-25 percent of US adults have it. Risks of Metabolic Syndrome Most mass index defined as the ratio between body weight in kilograms to the square of height in metres. (Weight in kg)/(height in meters) 2 < 17.5 Very Underweight > 20 (or 18.5) < 25 Normal > 25 Overweight or more > 30 Obese > 35 Morbidity obese Schizophrenics A Vulnerable Population Schizophrenics are a vulnerable population for metabolic syndrome because of the following factors: Smoking Obesity Diet higher in fat lower in fiber Sedentary lifestyle Increased prevalnce of diabetes Proneness to central obesity 4 Atypical Antipsychotics and Metabolic Syndrome Atypical antipsychotics cause : Weight gain Insulin resistance-diabetes Worsening lipid profile which predispose to metablic syndrome. 12-13 ADA* Consensus on Antipsychotic Drugs and Obesity and Diabetes Drug Weight Gain Diabetes Risk Dyslipidemia Clozapine + + + + + Olanzapine + + + + + Risperidone + + D D Quetiapine + + D D Aripirazole + Ziprasidone + Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society 33

DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 APRIL 2007 ADA* Consensus on Antipsychotic Drugs and Obesity and Diabetes: Monitoring Protocol Start 4 wks 8 wks 12 wks Quarterly 12 mths 5yrs Personal /family X X history Weight BMI X X X X X Waist circumference X X Blood Pressure X X X Fasting Glucose X X X Fasting lipid profile X X X X * American Diabetologists Association. According to the protocol more frequent assessments may be warranted based on clinical status. Obesity as a risk factor for antipsychotic noncompliance Studies have shown that greater the BMI greater is the risk for non-compliance for antipsychotic drugs. Possible Mechanisms Behind Weight Gain with Olanzapine Weight gain due to Olanzapine may be explained by the following mechanisms: Improved functioning-less self neglect, improved eating habits Increase in appetite-carbohydrate craving, sedation and decreased motor activity Altered adipose tissue-metabolism, fat composition and distribution Effect on neurotransmitters - 5HT, H1, DA, Alpha 1 blockade Increase in leptin and prolactin levels Role of Receptors in Appetite and Weight gain Receptors have been found to play an important part in regulating appetite and weight gain. The following receptors are involved: Decreased 5HT action-increased eating Noncomplaint Respondents According to BMI Category *P = 0.01 vs normal; Chi-square: P = 0.03; Test for linearity: P = 0.01 Schizophrenia population 34 Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society

APRIL 2007 DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 Decreased H1 action-increased eating Beta 3 adr energic-regulates energy metabolism and thermogenesis Leptin secreted by white adipose cells correlates highly with body fat mass. It also regulates insulin secretion and energy metabolism. Relationship between weight gain and base line BMI Some studies showed an inverse relationship between weight gain and baseline BMI. Whereas others gave contrary findings. Buckley et al reported that there was no significant association between body weight gain, changes in serum glucose level, Olanzapine dosage after three years study. 14 Medical Comorbidities with Bipolar Disorder Cardiovascular disease Relative cardiovascular mortality in male inpatients with bipolar disorder = 1.87 Obesity Central obesity is more common, especially with patients on antipsychotics Diabetes Prevalence = 9.9%; expected frequency = 3.4% Neurological disorders Migraine: prevalence = 25% of men, 27% of women; rate in men is almost 5x general population Atypical 52-Week Weight Gain Mean Change from Baseline Weight Effect of Antipsychotics on Glucose and Lipid Metabolism Clozapine Increased risk of diabetes, Risk of LDL, HDL and Olanzapine and reports of diabetic KA triglycerides Risperidone Discrepant results Risk of dyslipidemia is Quetiapine regarding risk of diabetes intermediate Ziprasidone Aripiprazole No apparent increase in risk, though these agents were released more recently (2001-02 versus 1989-9 Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society 35

DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 APRIL 2007 Chronic pain syndromes Correlates of Obesity in Patients with Bipolar Disorder Male Hypertension Arthritis Diabetes mellitus > 4 manic episode > 1 suicide attempt Exposure to > 1 weight-increasing psychotropic Limited occupational functioning Comorbid binge-eating disorder Risk for Hyperlipidemia There is accumulating empirical evidence and growing clinical concern that some of the newer antipsychotic medications may increase the risk of hyperlipidemia. Case reports have linked treatment with clozapine and olanzapine to hyperlipidemia that disappears when antipsychotic medications are discontinued. Medical record reviews further support a connection between clozapine and olanzapine and the increased risk of hypertriglyceridemia. Prospective resear ch fur ther suggests that antipsychotic medications may adversely affect serum lipids. 15 High Low-potency Typical antipsychotics Olanzapine Clozapine Low High-potency Typical antipsychotics Risperidone Ziprasidone Aripiprazole Mechanisms for Dyslipidemia with Antipsychotics Greatest effect is on triglycerides, with acute severe hypertriglyceridemia sometimes reported. Obesity/Excess caloric intake. Not a high association between weight gain and increases in serum trigycerides. Insulin resistance, diabetes. H1 Antagonism (increased appetite) Association between high affinity for the H1 receptor and weight gain. 5-HT2c antagonism Poor correlation; high affinity for ziprasidone which is weight and triglyceride neutral. Prevalence of Diabetes and Impaired Glucose Tolerance are Relatively High in Schizophrenia and Bipolar Disorder Rates of type II diabetes mellitus in schizophrenia reportedly are 2-4 times the general population. The association between antipsychotic medication treatment and hyperglycemia has been reported since the 1950s. There are many complex mechanisms involved that leads to glycemic dyscontrol including receptor involvement. The Receptor Density following diagram shows the receptor density in insulin resistant cell and schizophrenics have got insulin resistance. 17-19 Parameters Monitored in Patients on Atypicals Personal and family history of diabetes and cardiovascular disease (obesity, dyslipidemia, hypertention) BMI (weight and height) Waist circumference Blood pressure 36 Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society

APRIL 2007 DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 Fasting plasma glucose Fasting lipid profile In addition Patients with diabetes are monitored for glucose control; those with risk factors (obesity, family history of diabetes) are monitored for fasting glucose at baseline and periodically. Patients who develop polydipsia, polyuria, polyphagia, and weakness should also be monitored regularly. 20 Class Warning of Atypicals Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. The confounders are DM in schizophrenia, increasing incidence in population. Studies suggest an increased risk (of hyperglycemia related events) in patients treated with atypicals. But the precise relationship is not yet completely understood. The precise estimates for increased risk) are not available. Metabolic Dysregulation in Depression Depression is a risk factor for stroke and coronary artery disease independent of age, gender and lifestyle. The likelihood of developing myocardial infarction in depressed patients is four times that of the general population. The likelihood of stroke in depressed patients is 2.6 times that of the general population. Increased platelet activation, endothelial dysfunction, elevated inflammation markers and deficiencies in omega-3 fatty acids are supposed to contribute to the increased risk. Studies revealed that depressed subjects are 2.2 times as likely as depressed patients to develop diabetes. Depression impedes diabetes outcome by impeding functional impairment, decreasing glycemic control and increasing vascular complications. Weight Gain Associated with Tricyclic Antidepressants It is probably related to H1 antagonism. Tertriary amine TCA s are more potent H1 blockers and cause more weight gain. Weight Gain Associated with SSRI s Patients on SSRI s may have initial weight loss followed by weight gain. Down regulation of the 5HT2c receptor may be the cause of weight gain Weight Gain Associated with Antidepressants Common Often Occasional Rare or Never TCAs: Amitriptyline, Doxepin, Imipramine Mirtazapine TCAs: Desipramine, Nortriptyline SSRI: Paroxetine MAOI: Phenelzine Other SSRIs SNRIs MAOI: Tranylcypromine Nefazodone Weight Gain Associated with Mood Stabilizers Common Often Occasional Rare or never Weight loss Valproate Lithium carbonate Carbamazepine Lamotrigine Topiramate associated with SSRI s. As SSRI s are commonly prescribed a potentially large population may be experiencing the weight gain associated. Paroxetine is more likely than other SSRIs to be associated with weight gain. Other SSRIs appear largely similar, but head-to head comparisons are unusual. Weight Gain in Psychiatric Patients Clozapine and Olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Weight gain may be due to restoration of weight loss that might have occurred due to illness or due to dieting. Hypothyroidism might present a similar picture. Significant changes in lifestyle and medication-induced side effects may also cause weight gain. Careful history helps in identifying the cause of weight gain. Patients may be unaware of the cause of their weight gain as often there is no noticeable increase in appetite. Patients tend to blame themselves for overeating even when weight gain (and appetite) is drug-induced. 12,21 Conclusion Persons with high mental distress have a high prevalence of health risk behaviours. They are probably not getting optimal care for their medical conditions. The burden of their medical conditions Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society 37

DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 APRIL 2007 must impede their full r ecovery from their psychiatric illness. Health Outcomes are not part of recovery goals or mental health system design. Mental health service systems should assess and respond to health risks by Screening and organizing programs to address smoking, obesity, lack of exercise Screening for diabetes, hypertension, metabolic syndrome Integrating client specific health information into psychotropic medication decision making Making improvement of physical health as a part of mental health activities References 1. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salomen JT. The metabolic syndrome and total and cardiovascular disease mortality in middleaged men. JAMA 2002; 288 : 2709-2716. 2. Mc Evoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, Meltzer HY, Hsiao J, Stroup TS, Lieberman JA. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80 : 19-32. 3. Marc A., De Hert. Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication. Schizophrenia Res 2006; 83(1) : 87-93. 4. Sarafidis PA, Nilsson PM. The metabolic syndrome: a glance at its history. J Hypertens 2006; 24 : 621-626. 5. M De Hert, R van Winkel, D Van Eyck, L Hanssens, M Wampers, A Scheen, and J Peuskens. Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study. Clin Pract Epidemol Ment Health. 2006; 2 : 14. 6. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 (suppl 1) : 1-93. 7. Ilaria Tarricone, Michela Casoria: Metabolic risk factor profile associated with use of second generation antipsychotics: a cross sectional study in a community mental health center. BMC Psychiatry. 2006; 6 : 11. 8. Remington G. Schizophrenia, Antipsychotics, and the Metabolic Syndrome: Is there a Silver Lining? American Journal of Psychiatry 2006; 163 : 1132-1134. 9. Heiskanen T, Niskanen L, Lyytikainen R, Saarinen PI, Hintikka J: Metabolic syndrome in patients with schizophrenia. J Clin Psychiatry 2003; 64 : 575-579. 10. Mark Olfson. Hyperlipidemia following treatment with antipsychotic medications. American Psychiatry. 2006; 163 : 1821-1825. 11. Brown S, Inskip H, Barraclough B. Causes of the excess mortality of Schizophrenia. Br J Psychiatry 2000; 177 : 212-217. 12. Jim Rosack. Clinicians Urged to Better Monitor Drug-Related side effects Psychiatr News 2006; 41 (31). 13. Ya Mei Bai, Chao-Cheng Lin et al: Association of Initial Antipsychotic Response to Clozapine and Long-Term Weight Gain. American Journal of Psychiatry. 2006; 163 : 1276-1279. 14. Buckley PF, Miller DD, Singer B, Arena J, Stirewalt EM. Clinicians recognition of the metabolic adverse effects of antipsychotic medications. Schizophr Res 2005; 79 : 281-288. 15. Wayne S. Fenton, and Mark R. Chavez. Medication-Induced Weight Gain and Dyslipidemia in Patients with Schizophrenia. American Journal of Psychiatry. 2006; 163 : 1697-1704. 16. Almeras N, Despres JP, Villeneuve J, Demers MF, Roy MA, Cadrin C, Mottard JP, Bouchard RH: Development of an atherogenic metabolic risk factor profile associated with the use of atypical antipsychotics. J Clin Psychiatry 2004; 65 : 557-564. 17. Kohen D: Diabetes mellitus and Schizophrenia: historical perspective. Br J Psychiatry 2004; 184 (suppl 47) : S64-S66. 18. Cohn TA, Wolever T, Bois D, Zipursky RB, 38 Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society

APRIL 2007 DELHI PSYCHIATRY JOURNAL Vol. 10 No.1 Remington G: First episode and neuroleptic free patients with schizophrenia have reduced insulin sensitivity: a minimal model analysis. Schizophr Bull 2005; 31 : 197-198. 19. Zhong Zhao. Insulin receptor deficits in schizophrenia and in cellular and animal models of insulin receptor dysfunction. Schizophrenia Research 2006; 84(1) : 1-14. 20. David Straker, Christoph U. Correl. Cost- Effective Screening for the Metabolic Syndrome in Patients Treated with Second Generation Antipsychotic Medications. Am J Psychiatry 2005; 162 : 1217-1221. 21. Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry 2001; 62 (suppl 7) : 22-31. Delhi Psychiatry Journal 2007; 10:(1) Delhi Psychiatric Society 39