Why does zyprexa weight gain

Overweight is associated with reduced self-esteem, reduced quality of life and stigma. People taking antipsychotics regard weight gain as one of the most distressing side effects caused by their medication.

The fastest weight gain occurs in the first 6 months after starting an antipsychotic. Weight gain can continue after this but more slowly. There is no clear relationship between weight gain and antipsychotic dose, at least within the ranges usually used to treat mental health problems. The one exception is clozapine which is more effective than other antipsychotics in treatment resistant schizophrenia.

This is a form of schizophrenia in which psychotic symptoms e. The table shows the risk of weight gain with different antipsychotics. However, weight change can differ greatly from person to person. With any antipsychotic, some people may gain a lot of weight, some a moderate amount and some may not gain any weight or actually lose some weight. Greater weight gain during the first month of antipsychotic treatment tends to predict greater weight gain in the longer term.

Antipsychotics can increase glucose sugar and lipid fat levels in the blood. The drugs that do this the most tend to be the same ones that cause the most weight gain. A person starting antipsychotic medication for the first time is likely to gain more weight than someone starting the same medication who has previously taken other antipsychotics.

This is because weight will often have been put on with earlier antipsychotic treatment. This corresponds to people being treated by early intervention teams in the UK. The extra energy or calories are stored as body fat.

Many factors can affect this energy balance and lead to weight gain. The main way that antipsychotics cause weight gain is by stimulating appetite so that people feel hungry, eat more food and take in more calories. Some people taking antipsychotics report craving sweet or fatty food. The regulation of appetite and food intake is extremely complex and is controlled by part of the brain called the hypothalamus.

The hypothalamus integrates information it receives from other part of the brain and from hormones released from outside of the brain including fat adipose tissue and the gut.

These hormones include leptin and ghrelin but there are many others. Exactly how this complex system works and how antipsychotics disrupt it are not fully understood. Neurotransmitter receptors in the brain seem to play a part, with evidence implicating the serotonin 5-HT2C and 5-HT1A receptors, histamine H1 receptor and dopamine D2 receptor among others. Antipsychotics differ in their ability to block these receptors and this partly explains their different liability to cause weight gain.

Both olanzapine and clozapine, drugs with a high risk of weight gain, bind strongly to the histamine H1 and serotonin 5-HT2C receptors. The pharmacology of antipsychotics is not the only factor that determines their effect on weight.

As already mentioned, if a group of people take the same antipsychotic there will be differences between them in their subsequent weight change. This reflects differences between people in their diet, level of activity and genetic makeup.

Variations polymorphisms in a large number of genes, including the gene that codes for the 5-HT2C receptor, have been linked to susceptibility to gain weight with antipsychotics. It is the combined effect of these genes, rather that variation in a single gene, that is relevant to weight gain. In the future, it may be possible to conduct a simple blood test i. This could help people choose the best drug for their treatment.

However, such a test is not currently available. Decisions on choosing medication and managing weight, as with other areas of treatment, should be made jointly by a patient and their doctor. The main approaches to managing weight with antipsychotics are:.

Other approaches can sometimes help manage weight gain including adding certain medications to antipsychotics. These approaches are reviewed in a recent BAP Guideline that also considers the broader issue of reducing the risk of cardiovascular disease i.

Some people may consider stopping antipsychotic treatment due to weight gain. The issue of how long to continue antipsychotic treatment is complex. Space only allows some basic comments to be made here. Excess weight caused by an antipsychotic will usually be lost gradually after medication is stopped.

Weight put on for other reasons is likely to remain. The downside of stopping antipsychotics is an increased risk of becoming unwell, especially for people with schizophrenia and bipolar disorder. Sometimes relapse occurs suddenly with serious repercussions. A person should never stop their antipsychotic, or alter the dose, without discussing this first with their psychiatrist. Together, the patient and doctor should carefully consider the advantages and disadvantages of continuing medication, stopping medication and other options for managing mental health, weight gain and other side effects.

These will differ from person to person and reflect their medical history and current circumstances. The discussion should lead to a jointly agreed management plan that is tailored to the individual.

For some people stopping medication is a realistic option but for others it is inappropriate. If a decision is made to stop antipsychotic treatment, then the dose should be reduced gradually. Medication should not be stopped suddenly. A healthcare professional should monitor the person for signs and symptoms of relapse while the dose is reduced and after it is stopped.

For people with schizophrenia or psychosis, monitoring is recommended for at least two years after antipsychotics are stopped. A great deal of research is trying to improve outcomes for people with mental health problems.

This includes developing more effective medications with a lower risk of weight gain and other side effects. Lifestyle modification programmes have a modest benefit in reducing weight gain in people starting antipsychotics and helping those established on antipsychotics to lose weight. These interventions can be given to individuals or to groups or both approaches can be combined. Participants were encouraged to eat a healthier diet and spend at least 25 minutes per day doing moderate activity.

If psychosis, at least in some people, could be treated by giving antipsychotics for shorter periods than is current practice then it would reduce weight gain and other medication side effects. The RADAR trial is an ongoing randomised trial in the UK that compares a gradual and supported programme of antipsychotic reduction to maintenance antipsychotic treatment i. This approach has the advantage of avoiding antipsychotic side effects altogether.

This work is at an early stage and at the time of writing its effectiveness is not known, though initial results are promising. Nevertheless, it would widen treatment choice for some people and represent a major step forward in treating psychosis.

Antipsychotics are effective in treating schizophrenia and mania but can cause a range of side effects. Weight gain is a common and serious side effect, especially due to its impact on physical health.

Various interventions can help and a psychiatrist will be able to offer advice on these. Many people taking antipsychotics can lose some weight with simple changes to their diet and lifestyle. Losing even a small amount of weight can have important health benefits. Ongoing research is attempting to find ways to better manage or ideally avoid this problem. The BAP Guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment are available at: www.

An article reviewing these Guidelines is available at: www. Eur Psychiatry 24 6 BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol 30 8 Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind week comparison.

Am J Psychiatry 7 N Engl J Med Last updated: March PLoS One 9 12 : e The STRIDE weight loss and lifestyle intervention for individuals taking antipsychotic medications: a randomized trial. However, men receiving a low dose of quetiapine showed an average weight loss of 0. The investigators did not control for drugs prescribed to reduce weight gain or that could potentially affect weight, a potential limitation of the study. In addition, treatment duration and adherence may not have been captured fully.

Effects of long-term antipsychotics treatment on body weight: a population-based cohort study [published online November 14, ]. J Psychopharmacol. Show More. They had a significant increase in their respiratory rate Table 3. Subjects rated their hunger before the fMRI scan and after the first half of the experiment, but before they had their liquid breakfast.

Subjects' perception of hunger was close to 3 hungry before the scan and this did not change significantly before breakfast or with olanzapine treatment eFigure 4. During the scan, subjects rated their experience of the rewarding taste and the tasteless solution after each BOLD run. Their ratings of these liquids did not differ significantly after treatment with olanzapine eFigure 5.

This analysis revealed a number of expected regions in the inferior frontal gyrus, claustrum, insula, and caudate Figure 3 and Table 4 that showed greater response to cues predicting reward as compared with cues predicting tasteless liquid see Figure 4 for time course examples.

The time courses of the activations in these regions showed a consistent pattern of increased responses to the anticipation of reward and a decreased response to the tasteless solution cue after treatment with olanzapine Figure 4. This analysis again revealed a number of expected regions in the insula, caudate, putamen, amygdala, inferior frontal gyrus, middle frontal gyrus, and medial prefrontal cortex Figure 5 and Table 5.

As shown in Figure 6 , the time courses in these regions showed a greater response to the receipt of rewarding liquids as compared with the tasteless solution.

The time course of activations in these regions showed that in the inferior frontal gyrus, there was a decrease in activation to the rewarding taste after olanzapine treatment, while the response to the tasteless solution increased. In the caudate and putamen, the response to rewarding taste increased after olanzapine treatment while the response to the tasteless solution decreased Figure 6. To our knowledge, this is the first human study to look at the neural correlates of weight gain after a 1-week trial of an antipsychotic medication.

We were interested in characterizing the taste reward response underlying olanzapine-induced weight gain. Our study design allowed us to evaluate the impact of olanzapine on both the anticipatory and experiential aspects of a taste reward.

We found that our subjects gained weight, increased their food intake, and demonstrated an increase in their self-reported disinhibited eating behavior. Further, our imaging data showed an increase in the anticipatory reward responsivity toward food reward in the inferior frontal cortex, striatum, and anterior cingulate cortex.

We also found an increase in reward receipt responsivity in the caudate and putamen but a decrease in reward receipt responsivity in the lateral orbital frontal cortex, an area of the brain regarded as exercising inhibitory control on feeding. The adverse effects experienced by subjects in this study were consistent with other studies that administered olanzapine to healthy participants 41 - 43 and with the Food and Drug Administration—approved prescribing information for olanzapine.

A significant degree of weight gain has been reported in several studies investigating olanzapine-induced weight gain in healthy subjects 41 - 43 , 48 and in people with schizophrenia. However, this study detected insulin resistance and other metabolic changes that presage weight gain and there was a trend toward weight gain.

Subjects also had a significant increase in the amount of liquid breakfast they consumed after olanzapine treatment. A recent study investigated changes in food intake and energy expenditure in healthy, nonobese male subjects who took olanzapine for 15 days.

Another study that investigated olanzapine-induced weight gain in healthy subjects over a 2-week period found significant weight gain but not a significant increase in caloric consumption, although the means slightly increased. Participants also had significant increases in the Three-Factor Eating Questionnaire total score and the disinhibited eating factor subscale score.

The other 2 factor scores—eating restraint and hunger—were not significantly different. An elevated disinhibited eating score has been shown to predict weight gain in healthy adult subjects 78 , 79 and was related to obesity in otherwise healthy adolescents. Interestingly, subjects' perception of hunger did not change significantly after olanzapine treatment nor did their perception of the pleasantness of chocolate milk or V8 tomato juice Campbell Soup Company.

These findings contrast to the actual behavior of the subjects described earlier, as they consumed significantly more breakfast and gained weight after treatment with olanzapine. The neuroimaging data discussed later may shed some light into this dissociation between hunger perception and eating behavior. In sum, we found that 7 days of olanzapine treatment in our healthy, nonobese participants caused significant increases in their weight, self-reported disinhibited eating behavior, and amount of liquid breakfast they consumed, all while their hunger score and perceived pleasantness of the taste reward remained stable.

Consistent with prior research, we found that regions in the anterior insula, caudate, and inferior frontal cortex all showed increased BOLD responses to cues that predicted upcoming rewarding liquids, suggesting that our paradigm was successful in eliciting anticipatory reward—related responses.

All these regions showed enhanced responses to cues predicting rewarding liquids after olanzapine, while there was a decrease in activations elicited by the picture of the tasteless liquid.

Increased anticipatory responses in these reward regions to the anticipation of a pleasant taste have been associated with obesity in a number of studies. The experience of rewarding taste showed activations in the insula, amygdala, caudate, putamen, medial frontal cortex, and inferior frontal cortex.

All of these regions have been shown to respond to the experience of a taste reward in previous studies 24 , 36 , 82 , 84 and indicated that our paradigm was successful in eliciting taste receipt—related responses.

The regions that further interacted with olanzapine treatment were in the lateral orbital frontal cortex, caudate, and putamen.

In the caudate and putamen, activation to the experience of rewarding taste was enhanced after treatment with olanzapine. This enhanced activation in the striatum in our nonobese participants is in contrast to studies in obese individuals where either striatal hypoactivity 25 , 36 or no change in striatal activity was noted.

In the lateral orbital frontal cortex, the response to the actual experience of chocolate milk and tomato juice was diminished after treatment with olanzapine. This region is hypothesized to play a role in suppressing response to taste stimuli that were previously rewarding 28 , 74 and may play a role in satiety. This imbalance between the reward circuitry and circuits that inhibit prepotent responses to rewarding food 75 , 84 , 86 , 87 could extend our understanding of the mechanism of weight gain with atypical antipsychotic medications.

Further, these findings in our nonobese subjects are in general agreement with models of obesity, 17 , 25 albeit with an important difference: We found an increased response to food consumption in the dorsal striatum, while the literature in obese individuals points to a reduced response. As such, it is possible that this pattern is present in the initial stages of rapid weight gain and that we would find evidence for a decreased response to food in the striatum if we studied individuals taking olanzapine for longer periods.

Such reduction in striatal responsivity to the taste of milkshake was recently reported in healthy women after they had gained weight over a 6-month period. Our results contrast with a small pilot study with 8 subjects investigating monetary reward—related brain activation after a single dose of 5 mg of olanzapine.

However, this study used a monetary reward paradigm that did not distinguish reward anticipation from reward experience and focused on the acute 1-dose effect of olanzapine. Our study showed a more complex relationship of olanzapine treatment to an ecologically valid food reward after a steady-state dosing duration. There were several limitations of this study. First, we did not have a placebo control group and this limits our ability to conclusively demonstrate that the changes we observed were due to olanzapine treatment.

Second, because our unmedicated scan always preceded the scan with olanzapine, it is possible that habituation effects could be confounded with the olanzapine effects. However, the majority of the olanzapine-related anticipatory and receipt effects were in the direction of increased responses to rewarding food cues or to the receipt of food eg, in the caudate , which is in the opposite direction of the effects predicted by habituation over time.

Further, we also saw reduction of response in regions of the lateral orbital cortex that may play a role in inhibition. Thus, this interpretable pattern of both increased and decreased activation is not consistent with a general change in activity as a function of time.

Third, although participants had significant increases in their breakfast consumption, a food record and a measure of their physical activity would have yielded a more detailed picture.

Fourth, we used an ROI approach to analyze the data in view of our sample size and our a priori hypothesis that focused on the reward regions. Future research with a larger sample size may indicate changes in a wider array of brain regions. Finally, although subjects preferred both chocolate milk and tomato juice over the tasteless liquid, subjects had a stronger preference for chocolate milk over tomato juice. This presented a significant confound in assessing postfeeding satiety effects; hence, this aspect of the data could not be examined and differences in homeostatic regions such as the hypothalamus that differ as a function of satiety could not be explored.

With these limitations in mind, our study was the first, to our knowledge, to assess the neural mechanism underlying olanzapine-induced weight gain using an ecologically valid food-related reward paradigm. Our participants experienced significant weight gain, increased food intake, and disinhibition in their eating behavior. These changes in food-related cognition and behavior were accompanied by enhanced fMRI responses to food cues and the taste of food in a number of reward-related brain regions, including the inferior frontal cortex, striatum, and anterior cingulate.

Further, the use of olanzapine was associated with a decrease in activity to food receipt in the lateral orbital frontal cortex, a region thought to play a role in satiety responses. These fMRI changes suggested an enhanced anticipatory desire for food, an enhanced reward experience of consuming the anticipated food, and a compromised satiety-related mechanism.

This pattern of change after treatment with olanzapine provides a plausible set of mechanisms that may contribute to the weight gain commonly associated with this medication.

Our understanding of this common and unfortunate adverse effect of treatment with atypical antipsychotics would be enhanced by larger placebo-controlled studies that use comparator antipsychotic agents with low weight gain liability in patient populations; use continuous records of food intake and physical activity; use body composition assessments; explore prediction error—related effects, sex differences, and neural activity that correlates with the degree of weight gain; use appropriate satiety stimuli; and examine interactions with other malfunctions of the reward system such as substance abuse.

This could pave the way for targeted treatments that may help dial down the enhanced reward value of food while strengthening the inhibitory circuits that control food intake. Submitted for Publication: November 16, ; final revision received May 11, ; accepted June 11, Published Online: August 6, Corrected for errors on August 30, Author Contributions: Dr J.

Mathews has full access to all study data and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors had full access to all the data in the study. Financial Disclosure: Dr J. Mathews was in the speakers bureau of Janssen Pharmaceuticals and Bristol-Myers Squibb in the past 5 years, although he does not currently have any financial interest s or conflicts to disclose.

Role of the Sponsors: The National Alliance for Research on Schizophrenia and Depression, National Center for Research Resources, and National Institutes of Health had no further role in the design and conduct of the study; collection, management, analysis, and interpretation of data; or preparation, review, or approval of the manuscript. Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the National Center for Research Resources or National Institutes of Health.

Additional Contributions: We thank Richard Nagel for assistance with scanning the participants. Most importantly, we thank all the participants who provided time and effort to making this study possible.

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. View Large Download. Table 1. Demographic Characteristics. Table 2. Table 3. Table 4. Table 5. Schematic diagram of the experimental design. Pleasantness rating instruction and an example. Side effects experienced by the participants. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states.

Prev Chronic Dis. Obesity Silver Spring. Psychotic disorders, eating habits, and physical activity: who is ready for lifestyle changes? Psychiatr Serv. Pharmacoepidemiologic study of olanzapine in schizophrenia.

J Clin Psychiatry. Elevated levels of insulin, leptin, and blood lipids in olanzapine-treated patients with schizophrenia or related psychoses.

Nemeroff CB. Dosing the antipsychotic medication olanzapine. Antipsychotic-induced weight gain: A comprehensive reseach synthesis. Am J Psychiatry. A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder. Farver DK. Weight gain and long term complications with atypical antipsychotics.

South Dakota J Med. Wetterling T, Mussigbrodt HE. Weight gain: Side effect of atypical neuroleptics? J Clin Psychopharmacol. Gopalaswamy AK, Morgan R. Too many chronic mentally disabled patients are too fat. Acta Psychiatr Scand. Predictors of weight gain during olanzapine treatment. Eur Neuropsychopharmacol. Olanzapine versus haloperidol in the treatment of schizophrenia and schiz-oaffective and schizophreniform disorder: Results of an inter-national collaborative trial.

Conley R, Mahmoud R. Risperidone versus olanzapine in patients with schizophrenia and schizo-affective disorder. Risperidone study group; pp. Green B. Focus on olanzapine. Curr Med Res Opin. Berstein JG. Management of psychotropic drug induced obesity. Philadelphia: Lippincott; Body weight and leptin plasma levels during treatment with antipsychotic drugs. Association of olanzapine-induced weight gain with an increase in body fat.