Down the Rabbit Hole: When Medication Leads to Weight Gain

Abstract

A multi-centre study was designed to evaluate the efficacy of hydroxyzine in the treatment of patients presenting a generalized anxiety disorder (GAD). One hundred and thirty three patients, suffering from a GAD (according to DSM III-R criteria with 6 months duration criteria), were enrolled in a randomised, double-blind, hydroxyzine (50 mg/day) versus placebo, over a 4-week trial period.

By the end of the first week, the decrease of anxiety scores was significant for the hydroxyzine group, as compared to placebo (in respect of all rating criteria of anxiety). The statistical superiority for hydroxyzine continued to the end of the 4-weeks study period, and persisted at a further evaluation a week after abrupt discontinuation of active treatment.

The tolerance evaluation showed that side effects were reported in 52% of hydroxyzine group versus 35% of placebo group. The most commun side effects were sleepiness (28% vs 14% with placebo), weight gain (12% vs 10%), dry mouth (14% vs 5%), loss of concentration (9% vs 8%) and insomnia (9% vs 6%).

Sleepiness in the hydroxyzine group appeared during the first week and progressively disappeared later during treatment. We concluded that hydroxyzine at 50 mg/day produces a statistically and clinically significant anxiolytic effect, commencing during the first week of treatment and maintained throughout the 4-week period and after abrupt discontinuation without rebound of anxiety or withdrawal symptoms. The most commun side effect with hydroxyzine is transient sleepiness.

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Description and Brand Names

Thank you for your inquiry.

It has long been known that the administration of antihistamines can cause weight gain. In fact, one antihistamine, cyproheptadine, has been used for this purpose. There are many postulations as to why this occurs. One reason, which may be the most reasonable, is that histamine is known to reduce the appetite, and antihistamines, therefore, counteract this effect.

In a recent NHANES survey, antihistamine use was associated with obesity, and a study in the journal “Obesity,” (see abstract copied below) confirmed this and analyzed the use of over-the-counter antihistamines and their effect on weight gain. They found, as in the NHANES survey, that the use of over-the-counter antihistamines, including both fexofenadine and cetirizine, was associated with obesity.

Unfortunately, we know more about this association and the potential underlying reasons for it than we do about which antihistamines may be less likely to produce this effect. I know of no study comparing the effects of available antihistamines on weight gain and could find none on a literature search. Therefore, although it is not unlikely that some antihistamines may be more potent than others in this regard, the effect appears to be more class-related rather than drug-specific.

But because we have no available information on relative potency of antihistamines regarding their effect on weight gain, there is, to my knowledge, no information available to assist you in selecting a specific antihistamine that might be helpful and not produce this side effect. Therefore the only strategy available to you, if you wish to continue to use antihistamines, is to employ various agents via “trial and error.”

The other strategy of course would be to use alternative agents to supplement or replace antihistamine use. A thorough discussion of these drugs are available in two articles.
1.Morgan M and Khan DA. Annals of Allergy, Asthma, and Immunology 2008; 100:403-411.

2.Morgan M and Khan DA. Annals of Allergy, Asthma, and Immunology 2008; 100:51-526.

In summary, to my knowledge, there is no specific antihistamine which will not potentially cause the well-documented side effect of weight gain with regular use, and therefore the only alternative for you is to try different antihistamines in a “trial and error” fashion, or to supplement or substitute the use of antihistamines with alternative therapies. References and abstracts of references are copied below should you wish to read further about the issue of antihistamines and weight gain.

Thank you again for your inquiry and we hope this response is helpful to you.

Obesity
Volume 18, Issue 12, pages 2398–2400, December 2010
Abstract
The incidence of obesity in the United States has reached epidemic proportions. Previous research has shown several medications exert noticeable effects on body-weight regulation. Histamine-1 (H1) receptor blockers commonly used to alleviate allergy symptoms are known to report weight gain as a possible side effect. Therefore, we investigated the association between prescription H1 antihistamine use and obesity in adults using data from the 2005–2006 National Health and Nutrition Examination Survey (NHANES). Adults taking prescription H1 antihistamines were matched by age and gender with controls and compared on the basis of body measurements, plasma glucose, insulin concentrations, and lipid levels. Prescription H1 antihistamine users had a significantly higher weight, waist circumference, and insulin concentration than matched controls. The odds ratio (OR) for being overweight was increased in prescription H1 antihistamine users. H1 antihistamine use may contribute to the increased prevalence of obesity and the metabolic syndrome in adults given these medications are also commonly used as over-the-counter remedies.

Expert Opin Pharmacother. 2012 Dec;13(18):2613-24. doi: 10.1517/14656566.2012.742887. Epub 2012 Nov 10.
Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz.
Dabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khavidaki S.
Source
Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Enghelab Ave, Tehran, Iran.
Abstract
Introduction: More than 50% of HIV-positive patients experience neuropsychiatric adverse reactions following efavirenz therapy. Discontinuation of efavirenz due to its neuropsychiatric side effects has been reported in 2 — 13% of patients. Dizziness, headache, nightmares, abnormal dreams, mild cognitive difficulty, sleep disturbance (somnolence and insomnia), impaired concentration, depression, hallucination, delusion, paranoia, anxiety, agitation, aggressive behavior, mania, emotional labiality, catatonia, melancholia, psychosis, and fatigue are the most reported efavirenz adverse reactions.
Areas Covered: In this review, potential benefits of cyproheptadine in prevention and management of HIV/antiretroviral-associated neuropsychiatric complications are evaluated. The available evidence was collected by searching Scopus, PubMed, Medline, Cochrane central register of controlled trials, and Cochrane database systematic reviews.
Expert Opinion: Cyproheptadine is a cheap and safe drug that does not have significant interactions with antiretroviral drugs. Cyproheptadine’s common side effects including increasing appetite and weight gain can be useful in HIV-positive individuals with their decreased appetite and weight loss. There is limited evidence regarding the effectiveness of cyproheptadine in neuropsychiatric disorders. It is essential to evaluate cyproheptadine efficacy in the prevention and management of neuropsychiatric complications of HIV/antiretroviral infection in well-designed studies in the future.

Curr Med Chem. 2010;17(36):4587-92.
Neuronal histamine and its receptors: implication of the pharmacological treatment of obesity.
Masaki T, Yoshimatsu H.
Source
Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka,Yufu-Hasama, Oita, 879-5593, Japan.
Abstract
Obesity is the effect of imbalance between energy intake and expenditure and forms a fundamental basis of the metabolic syndrome. A number of substances implicated in the regulation of energy metabolism represent opportunities for anti-obesity drug development. Neuronal histamine and its receptors have been shown to regulate energy metabolism and are considered as anti-obesity targets. Several histamine receptor subtypes have been identified; of these, histamine H1 and H3 receptors (H1-R and H3-R) have been specifically recognized as mediators of energy intake and expenditure. In addition, several histamine drugs related to H1-R and H3-R, have been shown to attenuate body weight gain both in rodent and human. These results provide the reagents for histamine receptors biology and may find applications in the treatment of obesity and related metabolic disorders. In this review, the development of agonists and antagonists of histamine receptors are provided.

References:
Clineschmidt BV, Lotti VJ. Histamine: intraventricular injection suppresses ingestive behavior of the cat. Arch Int Pharmacodyn Ther 1973;206:288–298.PubMed, CAS, Web of Science® Times Cited: 67

Sakata T, Yoshimatsu H, Kurokawa M. Hypothalamic neuronal histamine: implications of its homeostatic control of energy metabolism. Nutrition 1997;13:403–411.

Kalucy RS. Drug-induced weight gain. Drugs 1980;19:268–278.

Sincerely,
Phil Lieberman, M.D.

YES!!! Within a few months I went from 110 pounds to 178. I have been using restrictive dieting and exercising several days a week, and still cannot lose the weight. I have a visit with my psychiatrist on the 27th of this month, and I plan to speak with him about this. No matter what he says, I will not be taking this medication anymore under any circumstances after I talk to him. This weight gain has destroyed my confidence and self-esteem. I look forward to getting off this medication and dropping all of this weight. So, to answer your question, yes because I am going through the EXACT same thing.

Many medications, including antidepressants, antipsychotics, mood stabilizers, corticosteroids, beta-blockers, hormonal contraceptives, insulin, and even medications for allergy such as diphenhydramine (Benadryl), cause weight gain—even considerable weight gain—in susceptible patients. Far more medications result in weight gain than in weight loss. Initially, there were only anecdotal reports of weight gain with prescription medications but the extent of the problem was delineated when Allison and his colleagues conducted comprehensive literature searches (Cheskin et al, 1999; Allison et al, 1999) almost 15 years ago and found medication-related weight gain was “under-recognized” by clinicians and sometimes resulted in patients’ noncompliance with treatment.

istock.com, DNY59, used with permission

Source: istock.com, DNY59, used with permission

How much weight is someone willing to gain when he or she is on a medication? That question was posed by Sansone and colleagues to a sample population of over 200 Midwestern, suburban (and primarily women) in a primary care practice. For either a medical or psychiatric non-life threatening condition, this sample would accept a weight gain of about 5 1/2 pounds. If the medical or psychiatric condition involved a life-threatening condition, people were able to tolerate a weight gain of 13 pounds or higher. Of note, though, in this particular sample, more than 5% were unwilling to gain any weight.

In other words, for some, any weight gain is intolerable, regardless of the efficacy of the medication prescribed. For others, though, it is not just an issue of aesthetics: weight gain produced by medication may lead to serious metabolic abnormalities such as insulin resistance, hypertension, abnormal blood lipid levels, and even overt type 2 diabetes in those genetically vulnerable. This is particularly common in the so-called second-generation antipsychotics.

istock.com, Zaretskaya, used with permission

Source: istock.com, Zaretskaya, used with permission

Medications can cause weight gain in the short term (within the first 8 to 12 weeks) and the long term (several months to a year), according to Hasnain and Vieweg, in the journal PostgraduateMedicine (2013.) There is a suggestion that those who gain weight in the first several weeks of treatment are more likely to continue to gain, though some medications like the selective serotonin reuptake inhibitors (SSRIs) result in some weight loss initially but ultimately weight gain over the year.

Why do some medications cause weight gain? There are several factors, and the more mechanisms involved, the more likely weight gain will occur. For example, some medications may cause an increase in appetite specifically by receptor blockade. Wysokiński and Kloszewska in a recent article in the Journal of Advanced Clinical Pharmacology (2014) reviewed the complex hormonal system involved in short-term satiety and long-term energy storage. These authors note that histamine H1 blockade and serotonin 5-HT2C receptor antagonism are responsible for the weight gain that is seen with antipsychotics such as clozapine (Clozaril), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal), as well as antidepressants such as some of the SSRIs, most notably with paroxetine (Paxil).

Because a medication such as aripiprazole (Abilify), used primarily to treat psychosis but also now marketed (and highly advertised on TV) as an adjunct for treatment of depression, is a partial agonist, rather than an antagonist, it is generally thought of as weight neutral and may sometimes be substituted for those that cause the most weight gain such as clozapine and olanzapine. H1 receptor blockade is also responsible for weight gain with antidepressants, such as mirtazapine (Remeron) and trazodone (Desyrel), or the antihistamine such as hydroxamine (Vistaril.)

Other medications increase appetite by a direct effect on the many hormones involved in appetite regulation, including leptin, ghrelin, and insulin. For example, some antipsychotics (e.g. clozapine and olanzapine) also block the action of leptin, resulting in increased, but ineffective levels of this hormone (leptin resistance) and accumulation of fat tissue. Both antipsychotics and antidepressants can also affect the levels of insulin, creating a state of insulin resistance and even an increased risk of type 2 diabetes. Wysokiński and Kloszewska caution, however, that changes in these hormones may be secondary to weight gain rather than the cause of weight gain.

Sometimes, medications don’t affect appetite but rather can change (i.e. decrease) a person’s resting metabolic rate and hence cause weight gain. This has been seen with the older tricyclic antidepressants such as imipramine (Tofranil). Further, tumor necrosis factor-alpha (TNF-α) is a cytokine that can also lead to weight gain with some of the antipsychotics such as clozapine and olanzapine, but also with lithium, amitriptyline (Elavil), and mirtazapine. Wysokiński and Kloszewska report that activation of this TNF-α system seems to occur early in treatment and might eventually become a sensitive marker that weight gain will occur.

Other mechanisms resulting in weight gain include drinking highly caloric beverages because of dry mouth that may accompany medication or even increased sleeping time due to the sedating effects of medication and hence less energy expenditure. Sometimes patients are taking several medications at once, and concomitant medications may interact in a way to increase weight gain. Further, ethnicity, gender, and age also contribute to differences in medications’ effects on weight. For example, some studies report that weight gain is more common in women and more likely to occur in those predisposed to excessive weight in general.

Many of these mechanisms involve mutations in specific genes and eventually genomic studies will lead to more specific individual recommendations for patients. For example, some patients are “poor metabolizers” and some are “ultra-rapid metabolizers,” according to Altar et al, writing in the International Review of Psychiatry (2013.)

Bottom line: Weight gain can occur in both the short and long term and may interfere with treatment compliance. Clinicians should monitor patients carefully for weight-related and metabolic changes, as well as educate patients regarding healthy lifestyle choices of diet and exercise. It is often possible to switch to a more weight neutral medication or be able to lower the dose of the offending medication. Eventually, there will be more widely available genetic screenings that will lead to individualized recommendations.

istock.com, Vlada_, used with permission

Source: istock.com, Vlada_, used with permission

Drug information provided by: IBM Micromedex

Before Using

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Breastfeeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

I was just prescribed hydroxyzine pamoate 25 mg once a day (transition from work that causes?

No, you don’t have to worry about weight gain. It is an antihistamines or some sort of allergy med. It will take 3 to 5 weeks to work and you’d probably need a higher dosage. It is kind of like a pill that they give you that never works. All the doctors are scared to give you what you need because of lawsuits. It might under long, long term help. Yet I have never heard of it actually working. I ask for something else if I were you. Good luck, good doctors are hard to find.

Hi, weight gain has been listed as a very common side effect from atarax. Apparently it causes an increased appetite but also there is talk about it altering your metabolism? From reading posts from people that are on antihistamine treatment, Benadryl appears to be much better regarding weight gain. I can’t personally testify this info, so maybe you should contact your doctor. I don’t think you are alone though. I have taken phenergan in the past and i didn’t notice weight gain.

Descriptions

Hydroxyzine is used to help control anxiety and tension caused by nervous and emotional conditions. It can also be used to help control anxiety and produce sleep before surgery. This medicine is also used to relieve the symptoms of an allergic reaction (eg, hives, itching skin) caused by chronic urticaria, and atopic and contact dermatoses).

Hydroxyzine is an antihistamine. It works by preventing the effects of a substance called histamine, which is produced by the body.

This medicine is available only with your doctor’s prescription.

This product is available in the following dosage forms:

Dosing

The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage forms (capsules or suspension):
    • To help control anxiety and tension:
      • Adults—50 to 100 milligrams (mg) 4 times a day.
      • Children 6 years of age and older—50 to 100 mg per day, divided in small doses.
      • Children younger than 6 years of age—50 mg per day, divided in small doses.
    • To relieve the symptoms of an allergic reaction:
      • Adults—50 to 100 milligrams (mg) 4 times a day.
      • Children 6 years of age and older—50 to 100 mg per day, divided in small doses.
      • Children younger than 6 years of age—50 mg per day, divided in small doses.
    • For controlling anxiety and produce sleep before surgery:
      • Adults—50 to 100 milligrams (mg) a day.
      • Children—Dose is based on body weight and must be determined by your doctor. The dose is usually 0.6 milligram (mg) per kilogram (kg) of body weight per day.

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary.

When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Amisulpride
  • Bepridil
  • Cisapride
  • Dronedarone
  • Mesoridazine
  • Pimozide
  • Piperaquine
  • Saquinavir
  • Sodium Oxybate
  • Sparfloxacin
  • Terfenadine
  • Thioridazine
  • Tranylcypromine
  • Ziprasidone
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