Drugs Associated with Weight Gain

Full update March 2015

The management of obesity is a multifaceted endeavor. Diet, exercise, and behavioral modification are all recommended, in addition to pharmacotherapy when indicated (i.e., individuals with BMI ≥27 kg/m² with comorbidity or BMI ≥30 kg/m²) or surgical intervention when indicated (i.e., individuals with BMI ≥35 kg/m² with comorbidity or BMI ≥40 kg/m².)¹ Unfortunately, a number of medications can actually contribute to weight gain.¹ Alternatives to these may need to be considered, especially for patients who are overweight or obese with diabetes, cardiovascular disease, or other obesity-related complications.¹ If no alternatives to these medications are available, consider using the lowest effective dose of the medication.¹ The following chart lists medications associated with weight gain as well as the mechanism for and the extent of weight gain. For patients who need medications to help lose weight, see our PL Chart, Drugs for Weight Loss.

—This list is not all-inclusive. When comparing weight gain between specific agents or drug classes, keep in mind that the data in this chart were selected from various sources and there may be variability in study design, patient characteristics, indication for treatment, length of therapy, etc.—

Drug Class	Mechanisms for Weight Gain Additional Comments	Reported Weight Gain with SELECTED Drugs
Anticonvulsants/Mood Stabilizers
Anticonvulsants	Mechanisms may include:² increased lipogenesis and decreased lipolysis decreased serum glucose carbohydrate craving reduced energy expenditure via enhanced GABA-mediated neurotransmission Possible mechanisms for weight gain with carbamazepine include:^2,15 water retention fat deposition due to increased appetite Weight gain with gabapentin and pregabalin appears to be dose-related^2,4,15 Lamotrigine, levetiracetam, and phenytoin are considered to be weight neutral¹ Topiramate and zonisamide can cause weight loss⁴⁰	Carbamazepine Average of 1.5 kg at six to eight months of follow-up¹ Up to two-thirds of patients taking carbamazepine may gain weight¹
Gabapentin Average of 2.2 kg after 1.5 months^1,3 More than one-half of patients taking gabapentin for one year or more may gain ≥5% of baseline weight, with almost one-fourth of patients gaining ≥10% of baseline weight^1,15
Pregabalin Average of 5.2 kg over two years in patients with diabetes⁴ One in six patients taking pregabalin for up to one year may gain ≥7% of baseline weight³⁷ Average of 1.4 kg (compared to 0.4 kg with placebo) in short-term studies⁴²
Valproic Acid Average of 2 kg (~3% of baseline weight) after one year⁵ Up to ~70% of patients taking valproic acid may gain weight.^5,15 Almost one-half of patients may gain >10% of baseline weight¹
Mood Stabilizers	Mechanisms may include:^6-8 increased thirst and consumption of high-calorie drinks changes in food preference leading to increased intake of sucrose fluid retention inhibition of thyroid hormone synthesis leading to decreased basal metabolic rate	Lithium Up to two-thirds of patients taking lithium may gain >5% of baseline weight^6,15
Antidepressants
Monoamine Oxidase Inhibitors	Mechanisms may include:⁹ carbohydrate craving edema The potential for weight gain with isocarboxazid or tranylcypromine is controversial^8,9	Phenelzine 20 kg over four months¹¹
Other	Mechanisms may include:^9,10,12,13 blockade of histamine, serotonin, and peripheral alpha receptors leading to increased appetite Bupropion may cause weight loss⁴⁰	Mirtazapine Average difference of 1.74 kg compared to controls over four to 12 weeks¹⁴ Average difference of 2.59 kg compared to controls after 12 weeks or more¹⁴ 7.5% of patients taking mirtazapine may gain ≥7% of baseline weight¹³
Selective Serotonin-Reuptake Inhibitors (SSRIs)	Mechanisms may include:^12,15 carbohydrate craving blockade of histamine and serotonin receptors leading to increased appetite Weight gain seems to be more likely with paroxetine than with other SSRIs.¹⁵ Others may be weight neutral.¹	Paroxetine Average difference of 2.73 kg compared to controls after 12 weeks or more¹⁴ One in four patients taking paroxetine might gain ≥7% of baseline weight¹⁵
Tricyclic Antidepressants (TCAs)	Mechanisms may include:^8,9 carbohydrate craving blockade of histamine, serotonin, and peripheral alpha receptors leading to increased appetite blockade of histamine receptors leading to sedation and decreased physical activity anticholinergic activity leading to dry mouth and increased consumption of high calorie drinks decreased basal metabolic rate Among TCAs amitriptyline seems to cause the most weight gain¹	Amitriptyline Average difference of 1.5kg compared to controls over four to 12 weeks¹⁴ Average difference of 2.4 kg compared to controls after 12 weeks or more¹⁴
Nortriptyline Average difference of 2 kg compared to controls after four to 12 weeks¹⁴ No statistically significant difference when compared to controls after 12 weeks or more¹⁴
Antihistamines
H₁-Blockers	Mechanisms may include:^1,15 blockade of histamine receptors leading to increased appetite, sedation, and decreased physical activity More potent agents (1^st generation) may be more likely to cause weight gain. Those with less CNS activity (most 2^nd generation) are recommended in order to limit weight gain.¹	Cetirizine >1 kg over three weeks¹⁶
Antihypertensives
Beta-blockers	Mechanisms may include:^17,18 decreased basal metabolic rate¹ decreased thermogenic response to food insulin resistance decreased lipolysis Selective agents or nonselective agents with a vasodilating component such as carvedilol or nebivolol seem less likely to cause weight gain¹ Weight gain appears to take place with short-term therapy (first few months) with no further weight increases with chronic therapy¹⁸	Atenolol Average of 0.6 kg (compared to -0.4 kg with placebo) over 24 months¹⁸
Propranolol Average of 3 kg (compared to 1.6 kg with placebo) over 24 months¹⁸
Vasodilators	Mechanism is fluid retention^19,20	Minoxidil 4.5 to 6.8 kg increase over one year¹⁹
Antipsychotics
First-generation Antipsychotics	Mechanisms may include:^8,9,21,22 blockade of dopamine, histamine, and serotonin receptors leading to increased appetite blockade of histamine receptors leading to sedation and decreased physical activity Although controversial, antipsychotic-induced weight gain does not appear to be dose-related⁸ First-generation agents tend to cause less weight gain than atypicals²³ Chlorpromazine causes more weight gain than other first-generation agents²³	Chlorpromazine Average difference of 0.55 kg compared to placebo over four to 12 weeks²⁴
Atypical Antipsychotics	Mechanisms may include:^8,9,21,22 blockade of dopamine, histamine, and serotonin receptors leading to increased appetite blockade of histamine receptors leading to sedation and decreased physical activity Weight gain is greater with clozapine and olanzapine, followed by iloperidone, quetiapine, and risperidone^3,24 Weight gain, if any, may be insignificant with aripiprazole, asenapine, and ziprasidone.^1,3,24 Lurasidone and paliperidone are also less likely to cause weight gain.²⁴	Clozapine Average difference of 0.65 kg compared to placebo over four to 12 weeks²⁴
Iloperidone 12% to 18% of patients on iloperidone gain ≥7% of baseline weight over four to six weeks⁴¹
Olanzapine Average difference of 0.74 kg compared to placebo over four to 12 weeks²⁴ Average of 2.4 kg after 30 days or more³ About one-third of patients on olanzapine gain >7% of baseline weight¹
Quetiapine Average difference of 0.43 kg compared to placebo over four to 12 weeks²⁴ Average of 1.1 kg after 30 days or more³ About 16% of patients on quetiapine gain >7% of baseline weight¹
Risperidone Average difference of 0.42 kg compared to placebo over four to 12 weeks²⁴ Average of 0.8 kg after 30 days or more³ About 14% of patients on risperidone gain >7% of baseline weight¹
Hormones
Corticosteroids	Mechanisms may include:²⁵ decreased glucose tolerance increased truncal adipose tissue Short-term use does not appear to cause weight gain²⁷	Corticosteroids Average of 5.52 kg over one year²⁶ 4% to 8% weight gain over one year³
Hormonal Contraception	Mechanism is unclear²⁸ Orals are less likely to cause weight gain than injectables.^1,3 For patients who have weight gain or edema with a combined hormonal contraceptive, improvement may be seen after two to three cycles.²⁹ Consideration can also be given to switching to a lower estrogen pill.³⁰ NuvaRing and implants (Implanon-U.S., Jadelle-U.S.) may cause slight weight gain³⁰	Medroxyprogesterone injectable Average difference of 1.9 +/- 3.5 kg compared to women with IUDs after one year of use²⁸
Other	Mechanism is increased appetite³¹	Megestrol 3.54 kg over 12 weeks (800 mg)³¹ 1.91 kg over 12 weeks (400 mg)³¹ 0.83 kg over 12 weeks (100 mg)³¹
Hypoglycemic Agents
Insulin	Mechanisms may include:^8,15,38,39 decreased glycosuria and reduced calorie loss in urine increased calorie intake increased lipogenesis and decreased lipolysis increased protein synthesis and increased intracellular amino acid influx anabolic effect on adipose and muscle tissue Most weight gain occurs during the first three months of use³⁹ Basal insulin appears less likely to cause weight gain than other regimens such as prandial insulin, possibly due to less compensatory eating^1,32,39 Adding a weight-neutral or weight-reducing drug such as metformin to insulin may have similar effects as insulin on glycemic control but without additional weight gain³	Insulin Average after three years, when insulin was added to metformin or a sulfonylurea:³² Basal regimen: 3.6 +/- 0.5 kg Biphasic regimen: 5.7 +/- 0.5 kg Prandial regimen: 6.4 +/- 0.5 kg
Meglitinides	Mechanisms may include:^8,15 increased calorie intake anabolic effect on adipose tissue Weight gain appears to be dose-related³³	Nateglinide Average of 0.3 kg and 0.9 kg with 60 mg TID and 120 mg TID, respectively (versus -0.7 kg with placebo) after 24 weeks³³
Repaglinide Average of 3 kg (versus -0.9 kg with metformin) over four to five months³⁴
Sulfonylureas	Mechanisms are the same as for insulin^8,15,39 Most weight gain seems to occur during the first year of treatment³⁹ Sulfonylureas are considered to cause less weight gain than insulin and similar weight gain to pioglitazone^35,39	Gliclazide (Canada) Average of 1.8 kg after 30 days or more³
Glimepiride Average of 2.1 kg after 30 days or more³
Glipizide Average of 2.2 kg after 30 days or more³
Glyburide Average of 2.6 kg after 30 days or more³
Tolbutamide Average of 2.8 kg after 30 days or more³
Thiazolidine-diones	Mechanisms may include:^15,37,39 increased appetite increased subcutaneous fat fluid retention Weight gain appears to be dose-related³⁶ Weight gain may be less when thiazolidinediones are used in combination with metformin³⁹	Pioglitazone Average of 2.6 kg after 30 days or more³
Rosiglitazone Average of 1 kg and 3.1 kg with 4 mg and 8 mg daily, respectively (compared to -0.9 kg with placebo) after 26 weeks³⁶

Drug Class

Mechanisms for Weight Gain
Additional Comments

Reported Weight Gain with SELECTED Drugs

Anticonvulsants/Mood Stabilizers

Anticonvulsants

Mechanisms may include:²

increased lipogenesis and decreased lipolysis
decreased serum glucose
carbohydrate craving
reduced energy expenditure via enhanced GABA-mediated neurotransmission

Possible mechanisms for weight gain with carbamazepine include:^2,15

water retention
fat deposition due to increased appetite

Weight gain with gabapentin and pregabalin appears to be dose-related^2,4,15

Lamotrigine, levetiracetam, and phenytoin are considered to be weight neutral¹

Topiramate and zonisamide can cause weight loss⁴⁰

Carbamazepine

Average of 1.5 kg at six to eight months of follow-up¹

Up to two-thirds of patients taking carbamazepine may gain weight¹

Gabapentin

Average of 2.2 kg after 1.5 months^1,3

More than one-half of patients taking gabapentin for one year or more may gain ≥5% of baseline weight, with almost one-fourth of patients gaining ≥10% of baseline weight^1,15

Pregabalin

Average of 5.2 kg over two years in patients with diabetes⁴

One in six patients taking pregabalin for up to one year may gain ≥7% of baseline weight³⁷

Average of 1.4 kg (compared to 0.4 kg with placebo) in short-term studies⁴²

Valproic Acid

Average of 2 kg (~3% of baseline weight) after one year⁵

Up to ~70% of patients taking valproic acid may gain weight.^5,15 Almost one-half of patients may gain >10% of baseline weight¹

Mood Stabilizers

Mechanisms may include:^6-8

increased thirst and consumption of high-calorie drinks
changes in food preference leading to increased intake of sucrose
fluid retention
inhibition of thyroid hormone synthesis leading to decreased basal metabolic rate

Lithium

Up to two-thirds of patients taking lithium may gain >5% of baseline weight^6,15

Antidepressants

Monoamine Oxidase Inhibitors

Mechanisms may include:⁹

carbohydrate craving
edema

The potential for weight gain with isocarboxazid or tranylcypromine is controversial^8,9

Phenelzine

20 kg over four months¹¹

Other

Mechanisms may include:^9,10,12,13

blockade of histamine, serotonin, and peripheral alpha receptors leading to increased appetite

Bupropion may cause weight loss⁴⁰

Mirtazapine

Average difference of 1.74 kg compared to controls over four to 12 weeks¹⁴

Average difference of 2.59 kg compared to controls after 12 weeks or more¹⁴

7.5% of patients taking mirtazapine may gain ≥7% of baseline weight¹³

Selective Serotonin-Reuptake Inhibitors
(SSRIs)

Mechanisms may include:^12,15

carbohydrate craving
blockade of histamine and serotonin receptors leading to increased appetite

Weight gain seems to be more likely with paroxetine than with other SSRIs.¹⁵ Others may be weight neutral.¹

Paroxetine

Average difference of 2.73 kg compared to controls after 12 weeks or more¹⁴

One in four patients taking paroxetine might gain ≥7% of baseline weight¹⁵

Tricyclic Antidepressants
(TCAs)

Mechanisms may include:^8,9

carbohydrate craving
blockade of histamine, serotonin, and peripheral alpha receptors leading to increased appetite
blockade of histamine receptors leading to sedation and decreased physical activity
anticholinergic activity leading to dry mouth and increased consumption of high calorie drinks
decreased basal metabolic rate

Among TCAs amitriptyline seems to cause the most weight gain¹

Amitriptyline

Average difference of 1.5kg compared to controls over four to 12 weeks¹⁴

Average difference of 2.4 kg compared to controls after 12 weeks or more¹⁴

Nortriptyline

Average difference of 2 kg compared to controls after four to 12 weeks¹⁴

No statistically significant difference when compared to controls after 12 weeks or more¹⁴

Antihistamines

H₁-Blockers

Mechanisms may include:^1,15

blockade of histamine receptors leading to increased appetite, sedation, and decreased physical activity

More potent agents (1^st generation) may be more likely to cause weight gain. Those with less CNS activity (most 2^nd generation) are recommended in order to limit weight gain.¹

Cetirizine

>1 kg over three weeks¹⁶

Antihypertensives

Beta-blockers

Mechanisms may include:^17,18

decreased basal metabolic rate¹
decreased thermogenic response to food
insulin resistance
decreased lipolysis

Selective agents or nonselective agents with a vasodilating component such as carvedilol or nebivolol seem less likely to cause weight gain¹

Weight gain appears to take place with short-term therapy (first few months) with no further weight increases with chronic therapy¹⁸

Atenolol

Average of 0.6 kg (compared to -0.4 kg with placebo) over 24 months¹⁸

Propranolol

Average of 3 kg (compared to 1.6 kg with placebo) over 24 months¹⁸

Vasodilators

Mechanism is fluid retention^19,20

Minoxidil

4.5 to 6.8 kg increase over one year¹⁹

Antipsychotics

First-generation Antipsychotics

Mechanisms may include:^8,9,21,22

blockade of dopamine, histamine, and serotonin receptors leading to increased appetite
blockade of histamine receptors leading to sedation and decreased physical activity

Although controversial, antipsychotic-induced weight gain does not appear to be dose-related⁸

First-generation agents tend to cause less weight gain than atypicals²³

Chlorpromazine causes more weight gain than other first-generation agents²³

Chlorpromazine

Average difference of 0.55 kg compared to placebo over four to 12 weeks²⁴

Atypical Antipsychotics

Mechanisms may include:^8,9,21,22

blockade of dopamine, histamine, and serotonin receptors leading to increased appetite
blockade of histamine receptors leading to sedation and decreased physical activity

Weight gain is greater with clozapine and olanzapine, followed by iloperidone, quetiapine, and risperidone^3,24

Weight gain, if any, may be insignificant with aripiprazole, asenapine, and ziprasidone.^1,3,24 Lurasidone and paliperidone are also less likely to cause weight gain.²⁴

Clozapine

Average difference of 0.65 kg compared to placebo over four to 12 weeks²⁴

Iloperidone

12% to 18% of patients on iloperidone gain ≥7% of baseline weight over four to six weeks⁴¹

Olanzapine

Average difference of 0.74 kg compared to placebo over four to 12 weeks²⁴

Average of 2.4 kg after 30 days or more³

About one-third of patients on olanzapine gain >7% of baseline weight¹

Quetiapine

Average difference of 0.43 kg compared to placebo over four to 12 weeks²⁴

Average of 1.1 kg after 30 days or more³

About 16% of patients on quetiapine gain >7% of baseline weight¹

Risperidone

Average difference of 0.42 kg compared to placebo over four to 12 weeks²⁴

Average of 0.8 kg after 30 days or more³

About 14% of patients on risperidone gain >7% of baseline weight¹

Hormones

Corticosteroids

Mechanisms may include:²⁵

decreased glucose tolerance
increased truncal adipose tissue

Short-term use does not appear to cause weight gain²⁷

Corticosteroids

Average of 5.52 kg over one year²⁶

4% to 8% weight gain over one year³

Hormonal Contraception

Mechanism is unclear²⁸

Orals are less likely to cause weight gain than injectables.^1,3 For patients who have weight gain or edema with a combined hormonal contraceptive, improvement may be seen after two to three cycles.²⁹ Consideration can also be given to switching to a lower estrogen pill.³⁰

NuvaRing and implants (Implanon-U.S., Jadelle-U.S.) may cause slight weight gain³⁰

Medroxyprogesterone injectable

Average difference of 1.9 +/- 3.5 kg compared to women with IUDs after one year of use²⁸

Other

Mechanism is increased appetite³¹

Megestrol

3.54 kg over 12 weeks (800 mg)³¹

1.91 kg over 12 weeks (400 mg)³¹

0.83 kg over 12 weeks (100 mg)³¹

Hypoglycemic Agents

Insulin

Mechanisms may include:^8,15,38,39

decreased glycosuria and reduced calorie loss in urine
increased calorie intake
increased lipogenesis and decreased lipolysis
increased protein synthesis and increased intracellular amino acid influx
anabolic effect on adipose and muscle tissue

Most weight gain occurs during the first three months of use³⁹

Basal insulin appears less likely to cause weight gain than other regimens such as prandial insulin, possibly due to less compensatory eating^1,32,39

Adding a weight-neutral or weight-reducing drug such as metformin to insulin may have similar effects as insulin on glycemic control but without additional weight gain³

Insulin

Average after three years, when insulin was added to metformin or a sulfonylurea:³²

Basal regimen: 3.6 +/- 0.5 kg
Biphasic regimen: 5.7 +/- 0.5 kg
Prandial regimen: 6.4 +/- 0.5 kg

Meglitinides

Mechanisms may include:^8,15

increased calorie intake
anabolic effect on adipose tissue

Weight gain appears to be dose-related³³

Nateglinide

Average of 0.3 kg and 0.9 kg with 60 mg TID and 120 mg TID, respectively (versus -0.7 kg with placebo) after 24 weeks³³

Repaglinide

Average of 3 kg (versus -0.9 kg with metformin) over four to five months³⁴

Sulfonylureas

Mechanisms are the same as for insulin^8,15,39

Most weight gain seems to occur during the first year of treatment³⁹

Sulfonylureas are considered to cause less weight gain than insulin and similar weight gain to pioglitazone^35,39

Gliclazide (Canada)

Average of 1.8 kg after 30 days or more³

Glimepiride

Average of 2.1 kg after 30 days or more³

Glipizide

Average of 2.2 kg after 30 days or more³

Glyburide

Average of 2.6 kg after 30 days or more³

Tolbutamide

Average of 2.8 kg after 30 days or more³

Thiazolidine-diones

Mechanisms may include:^15,37,39

increased appetite
increased subcutaneous fat
fluid retention

Weight gain appears to be dose-related³⁶

Weight gain may be less when thiazolidinediones are used in combination with metformin³⁹

Pioglitazone

Average of 2.6 kg after 30 days or more³

Rosiglitazone

Average of 1 kg and 3.1 kg with 4 mg and 8 mg daily, respectively (compared to -0.9 kg with placebo) after 26 weeks³⁶

Project Leader in preparation of this PL Detail-Document: Stacy A. Hester, R.Ph., BCPS, Assistant Editor

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Cite this document as follows: PL Detail-Document, Drugs Associated with Weight Gain. Pharmacist’s Letter/Prescriber’s Letter. April 2015.

Drugs Associated with Weight Gain

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