Download Drug-Induced Weight Gain: A Review for Pharmacy

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
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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
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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
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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.
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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
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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
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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-
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causing agent, the use of other pharmacological agents to help control weight
gain may be considered.
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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.
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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.
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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
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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
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