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Drug-Induced Weight Gain: A Review for Pharmacy Technicians Darrell Hulisz, RPh, PharmD Associate Professor of Family Medicine Case Western Reserve University School of Medicine Associate Clinical Professor of Pharmacy Practice Ohio Northern University College of Pharmacy CPT Robert Brutcher, BS, PharmD Clinical Pharmacist, United States Army ContinuingEducation.com, Inc., is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is acceptable for 1.0 hours of Continuing Education Credits (0.1 CEUs) for Pharmacy Technicians ONLY. ACPE Program I.D. Number: 312-000-04-011-H04 The price of this program is: $7.00 Release Date: 5/12/2004 Address correspondence to: Dr. Darrell Hulisz University Family Medicine Foundation 11100 Euclid Avenue Cleveland, OH 44106 Office: (216) 844-3129 Email: [email protected] 1 Drug-Induced Weight Gain: A Review for Pharmacy Technicians Learning Objectives: 1. List common medications that are associated with weight gain 2. Explain the proposed mechanisms of drug-induced weight gain 3. Describe potential interventions that can limit the extent of drug-induced gain 4. Understand the limitations of clinical data used to determine a drug’s potential to cause weight gain 2 Introduction Weight gain associated with drug therapy is an increasing concern of health care professionals and, more importantly, patients affected. Patients can be adversely affected by drug-induced weight gain both physically and psychologically. Obesity and being overweight may decrease well-being, but also may increase morbidity and mortality.1 Weight gain results from an imbalance between energy intake and total energy expenditure. Numerous medications can, through different mechanisms, contribute to weight gain. However, the magnitude and onset of weight gain is not always predictable. General clinical parameters that might help predict drug-induced weight gain include the following: dose and length of therapy, duration of illness, clinical response, age, gender, cigarette smoking, BMI, environmental factors, and appetite.1 Pharmacy technicians should know which drugs have the potential to cause weight gain in order to effectively counsel patients. Thus, this article will discuss selected drugs associated with weight gain, and their potential mechanism for inducing weight gain. Drugs discussed herein include antipsychotics, antidepressants, valproate, insulin, and thiazolidinediones. This article only represents a handful of agents inducing weight gain, while others, including corticosteroids, and other fluid retaining agents will not be discussed. Drug treatment of psychiatric disorders has often been tagged with the adverse effect of marked weight gain. Weight gain in patients with schizophrenia was mentioned by clinicians as early as 1919, and in the 1950’s the first report of weight problems was published in association with the use of chlorpromazine.2 The problem of weight gain poses the additional challenge of patients who may potentially discontinue therapy. A study by Berken et al., showed that during a 6month treatment course with tricyclic antidepressants, 44% of the patients on amitriptyline and 70% of those on nortriptyline stopped taking their medication due to excessive weight gain.3 The atypical anti-psychotics have also become well known to cause weight gain considerably higher than the typical antipsychotics. Fontaine et al., estimated the consequences of antipsychotic treatment-induced weight gain on health and mortality and predicted 2335 additional causes of diabetes mellitus, 9456 cases of hypertension, and 662 additional deaths among 100,000 schizophrenic patients within 10 years. Possible mechanisms of drug-induced weight gain Several plausible mechanisms of drug induced weight gain have been postulated. Zimmermann et al., present a comprehensive review of the possible mechanisms of weight gain.1 Many psychiatric disorders are associated with weight changes, most commonly weight loss. Therefore, a possible mechanism for weight gain associated with therapy might reflect the restoration of normal body weight. Also, drug-induced weight gain is commonly preceded by a sudden 3 increase of appetite, specifically for sweet and fatty foods.1 Tricyclic antidepressants are associated with carbohydrate craving which probably develops from increased alpha-noradrenergic activity and histamine blockade.5 It has also been suggested that drugs inducing weight gain might interfere with the function of specific central nervous feedback systems regulating appetite and food intake. Also implicated are the effects on the central nervous system and the monoamines. Alpha-adrenergic neurotransmission is thought to stimulate appetite, while beta-adrenergic, histaminergic, dopaminergic, and serotonergic signal transduction confers satiety.1 Drugs which possess anticholinergic properties may cause dry mouth and increased thirst. Patients drinking high calorie drinks to quench their thirst may have significant weight gain. So the potential for certain drugs to affect these systems may explain the associated weight gain. A decrease in resting metabolic rate also plays a role in weight gain. Basal energy turnover can account for as much as 70% of daily energy expenditure. A small change in this basal metabolic rate may have a considerable impact on body weight. Finally, some drugs may induce weight gain by effects on glucose metabolism. Certain drugs with this possible mechanism include TCA’s, lithium, and antipsychotics. Zimmermann et al., also discuss the potential role of the tumor necrosis factor system in drug induced weight gain.1 These represent potential mechanisms for drug-induced weight gain, all of which need to be further studied. Antipsychotics Most of the classical antipsychotics result in weight gain, the extent of which differs between compounds without any clear correlation with antipsychotic potency or chemical structure.1 Recently, considerable attention was given to the atypical antipsychotics and their ability to induce weight gain. Many antipsychotics demonstrate H1 antagonism properties that ultimately result in sedation and have the potential to induce weight gain.2 Wirshing et al., reported a relationship between an antipsychotics H1 receptor affinity and maximum weight gain.6 Another possible underlying mechanism might be the ability of these drugs interference with glucose metabolism. Clozapine use has been associated with glucose intolerance and elevated insulin serum levels.7 Substantial weight gain has been associated with the use of clozapine. Among patients with schizophrenia, obesity was more frequently observed in clozapinetreated patients than in patients treated by other atypical antipsychotics or conventional antipsychotics.7-8 Umbricht et al., showed that 60% of patients had a weight gain greater than 10% of baseline weight in 12 months when being treated with clozapine.8 A review by Wetterling reported that the increase in bodyweight was significantly higher and occurred more frequently in patients receiving clozapine than patients being treated with haloperidol.7 This review also concluded that the weight gain associated with clozapine occurred in the first 12 weeks of therapy. 4 Weight gain associated with olanzapine has been associated with an increase in weight comparable to clozapine.9 A review of four studies showed that patients treated with olanzapine had a dose-related increase in weight. In this review, 40.5% of patients receiving olanzapine gained more than 7% of their baseline weight.9 Patients treated with olanzapine reported a higher and more frequent increase in weight than patients treated with haloperidol or risperidone.7 Risperidone has also been associated with weight gain. Owens et al., showed a mean weight gain of 1-2 kg after 8 weeks of therapy.10 A meta-analysis by Song showed bodyweight increases more frequently in patients receiving risperidone than in patients receiving typical antipsychotics.11 This weight gain however is less than that seen with clozapine or olanzapine therapy. There is mixed data on weight effects caused by ziprasidone. It has been show to be associated with minimal weight loss, minimal weight gain, or no effect at all.2 A review by Wetterling discusses that there are only slight changes in bodyweight which have been reported with ziprasidone treatment.7 More studies need to be conducted for further determination of effects of ziprasidone on body weight. Studies looking at quetiapine are fairly short-term, making it difficult to determine effects on weight. Results determining bodyweight changes during quetiapine treatment showed a wide variation in effects on bodyweight, but weight gain was higher than that seen with haloperidol or placebo treatment.7 The new agent aripiprazole has recently been studied for its effect on weight gain. Recent studies revealed no statistically significant mean changes in body weights versus placebo.12 Antidepressants Clinicians have been cautioned to consider potential beneficial or detrimental effects on appetite and weight when choosing among available antidepressants for geriatric depression.5 The probability and extent of weight gain appear to differ substantially between individual tricyclic antidepressants (TCA).1,5 TCA’s have been proposed to induce weight gain by causing carbohydrate craving and increased appetite.5 The monoaminoxidase inhibitors (MAO-I) have also been shown to have an effect on body weight. Balon et al., reported that phenelzine induced a weight gain at an extent comparable to that of imipramine.13 The newer antidepressant mirtazapine has also been associated with the potential to cause a considerable weight gain. Burrows and Kremer showed that mirtazapine was associated with increased appetite when compared to placebo (11% vs. 2%, respectively), and an increased incidence of weight gain (10% vs. 1%, respectively).14 SSRI’s have been proposed to have weight sparing, or even weight reducing effects. A proposed mechanism for these effects is that SSRI’s may induce nausea, and may therefore be considered to have an anorexic effect in the hypothalamic satiety center.5 A recent study by Sussman et al., showed that 5 weight loss appears to occur only during the initial weeks of treatment and may be followed by weight gain.15 Paroxetine is the SSRI which was most frequently associated with weight gain. In a double-blind placebo-controlled study by Fava et al., it was reported that there was a significant mean increase in body weight of 3.6% compared to baseline, while patients on sertraline or fluoxetine showed no significant weight gain.16 Rigler et al., found that SSRI use is as likely to be associated with weight gain as it is with loss, with even this finding being of marginal significance.5 Mood stabilizers: valproate and carbamazepine Valproate leads to substantial weight gain in as many as 50% of patients and may necessitate discontinuation of therapy.17 The mechanisms underlying this weight gain remain unknown. Valproate induced weight changes may be a result of either increased energy intake (increased appetite), decreased total energy expenditure, or both. Gidal et al., suggest the weight gain associated with valproate may be due to its ability to inhibit lipid oxidation resulting in decreased resting energy expenditure.17 Their studies showed that patients treated with valproate have measured resting energy expenditures that are significantly decreased as compared with predicted expenditures, suggesting patients treated with valproate are hypometabolic. Energy expenditure difference was marginal, but could ultimately lead to significant weight gain.17 Weight gain has also been associated with carbamazepine treatment. A report of four cases described the development of increased appetite and food intake, with carbamazepine treatment, resulting in weight gain of 7-15 kg in two months, reversibly only with discontinuation of drug treatment.18 Diabetic agents- Insulin and Thiazolidinediones There are three main concerns existing for insulin therapy, including the increased risk of cardiovascular disease, weight gain, and increased chance of hypoglycemia. Weight gain has frequently been associated with insulin therapy. In the UKPDS, weight gain was shown to be greater in the group who was intensely treated with insulin when compared to the group who was treated with conventional insulin therapy.19 Even though this study showed a greater increase in weight gain in the group treated intensely with insulin, there were no increased cardiovascular outcomes shown.19 Weight gain is a problem shared by other agents used in the treatment of diabetes as well. Thiazolidinediones (TZD’s), including pioglitazone and rosiglitazone, are insulinsensitizing agents being widely used to treat patients with type II diabetes mellitus. Fluid retention has become known as an adverse effect of therapy with TZD’s. In a study by Wilson-Tang et al., fluid retention was defined as an involuntary weight gain of over 10 pounds from baseline at any point within 12 6 months after initiation with a TZD.20 Weight gain is likely to be multifactorial, and could be the result of increased adipogenesis, increased appetite and edema, however the exact mechanism remains unclear.21 Weight gain may also be a result of improved glycemic control and decreased urinary caloric loss.22 Fluid retention (weight gain) usually results within the first few months of initiating drug therapy. The fluid retention seen is usually reversible with discontinuation of therapy. Limitations There are conflicting data concerning weight gain induced by certain drugs, including antdepressants. Especially of concern are the SSRI’s. Rigler et al., showed that weight changes in both directions may be somewhat more common among SSRI users, but the magnitude of this effect is small and of marginal significance.5 Also, many of the studies done do not record baseline weights, so weight gain is based on the patients account of initial weight. Some conclusions are also made on studies that also only lasted 6 weeks. In this case more longterm studies need to be completed describing the changes in bodyweight associated with certain drugs. Conclusions Weight gain and obesity have been associated with increased morbidity from coronary heart disease, diabetes mellitus, hypertension, gallbladder disease and some forms of cancer, and have many health implications, both physical and psychological.2,7 Also, bodyweight gain is associated with decreased compliance and an increased incidence of patients refusing further therapy. Therefore, pharmacists and physicians should consider the weight gain potential of antipsychotics in schizophrenic patients who are at increased risk for metabolic and weight gain abnormalities. However, there is a lack of data proving a relationship between the dosages of the atypical antipsychotic used and weight gain, compounding the difficulty in choosing appropriate therapy. Many of the studies showed that weight gain associated with atypical antipsychotic treatment could not be controlled with diet alone, giving health providers another concern with therapy. Patients treated with drugs that have the potential to induce weight gain should be encouraged to reduce their total daily caloric and fat intake. As discussed these measures may have little or no role in controlling the drug-induced weight gain, but can help reduce risk factors associated with being overweight. Drugs with antihistaminergic properties may cause sedation, resulting in reduced mobility. Patients should be encouraged to maximize their daily physical activity to increase their total energy expenditure. If therapy is necessary with a weight- 7 causing agent, the use of other pharmacological agents to help control weight gain may be considered. 8 References 1. Zimmermann U, Kraus T, Himmerich H, Schuld A, Pollmacher T. Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatric Research 2003;37:193-220. 2. Tardieu S, Micallef J, Gentile S, Blin O. Weight gain profiles of new antipsychotics: public health consequences. Obesity Reviews 2003;4:129-138. 3. Berken GH, Weinstein DO, Stern WC. Weight gain. a side-effect of tricyclic antidepressants. Journal of Affective Disorders 1984;7:133-138. 4. Fontaine KR, Heo M, Harrigan EP, Shear CL, Lakshminarayanan M, Casey DE, Allison DB. Estimating the consequences of antipsychotic induced weight gain on health and mortality rate. Psychiatry Research 2001; 101: 277-288. 5. Rigler SK, Webb MJ, Redford L, Brown EF, Zhou J, Wallace D. Weight outcomes among antidepressant users in nursing facilities. J Am Geriatr Soc 2001; 49:49-55. 6. Wirshing DA, Wirshing WC, Kysar L, Berisford MA, Goldstein D, Pashdag J, Mintz J, Marder SE. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999;60:358-363. 7. Wetterling T. Bodyweight gain with atypical antipsychotics: a comparative review. Drug Safety 2001;24:59-73. 8. Umbricht DS, Pollack S, Kane JM. Clozapine and weight gain. J Clin Psychiatry 1994;55:157-160. 9. Nemeroff CB. Dosing the antipsychotic medication olanzapine. J Clin Psychiatry 1997;58:13-17. 10. Owens DG. Extrapyramidal side effects and tolerability of resperidone: a review. J Clin Psychiatry 1994;55:29-35. 11. Song F. Risperidone in the treatment of schizophrenia: a meta-analysis of randomized controlled trials. J Psychopharmacol 1997;11:65-71. 12. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbnroff DL, Ali MW. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-771. 13. Balon R, Yeragani VK, Pohl R, Merlos B, Sherwood P. Changes in appetite and weight during the pharmacological treatment of patients with panic disorder. 9 Can J Psychiatry 1993;38:19-22. 14. Burrows GD, Kremer CM. Mirtazapine: clinical advantages in the treatment of depression. J Clin Psychopharmacol 1997;17:34-39. 15. Sussman N, Ginsberg DL. Weight effects of nefazodone, buproprion, mirtazapine, and venlafaxine: A review of the available evidence. Primary Psychiatry 2000;7:33-48. 16. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry 2000;61:863-867. 17. Gidal BE, Anderson GD, Spencer NW, Maly MM, Murty J, Pitterle ME, Collins DM, Davis LA. Valproate-associated weight gain: Potential relation to energy expenditure and metabolism in patients with epilepsy. Journal of Epilepsy 1996;9:234-241. 18. Lampl Y, Eshel Y, Rapaport A, Sarova-Pinhas I. Weight gain, increased appetite, and excessive food intake induced by carbamazepine. Clinical Neuropharmacology 1991;14:251-255. 19. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type II diabetes. Lancet 1998;352:837-853. 20. Wilson-Tang WH, Francis GS, Hoogwerf BJ, Young JB. Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure. J Am Coll Cardiol 2003;41:1394-1398. 21. O’Moore-Sullivan TM, Prins JB. Thiazolidinediones and type II diabetes: new drugs for an old disease. JMA 2002;176:381-386. 22. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 2001;134:61-71. 10 Continuing Education Examination 1. An additional benefit of atypical antipsychotics versus typical antipsychotics is their characteristic of causing less weight gain. a. True b. False 2. H1 antagonism demonstrated by many antipsychotics may result in sedation and have potential to induce weight gain a. True b. False 3. Recent studies revealed no statistically significant mean changes in body weights of patients receiving aripiprazole versus placebo. a. True b. False 4. Paroxetine is the SSRI which was most frequently associated with weight gain. a. True b. False 5. Fluid retention seen in patients being treated with thiazolidinediones (TZD’s) is usually irreversible, even with discontinuation of therapy. a. True b. False 6. All of the following are possible mechanisms by which medications may cause weight gain except: a. increased carbohydrate craving b. a decrease in resting metabolic rate 11 c. highly fat soluble inert ingredients of medications d. effects on glucose metabolism 7. Obesity was more frequently observed among schizophrenic patients receiving which antipsychotic? a. clozapine b. risperidone c. quetiapine d. haloperidol 8. Which mood stabilizer is associated with a possible hypometabolic state leading to obesity? a. valproate b. lithium c. carbamazepine d. topiramate 9. Weight gain and obesity have been associated with increased morbidity from all of the following except: a. schizophrenia b. CAD (coronary heart disease) c. diabetes mellitus d. gallbladder disease 10. The weight gain seen with atypical antipsychotics usually cannot be controlled by diet alone: a. True b. False 12