Antipsychotic medication and weight gain

Introductio­­n

This article, written primarily for people with mental health problems and their carers, is about weight gain with antipsychotic medication. Antipsychotics are a group of drugs that are mainly used to treat schizophrenia and manic episodes in bipolar disorder. In both conditions, they are effective in treating symptoms and reducing the risk of a person becoming unwell again (i.e. having a relapse). Some antipsychotics are helpful in other mental health disorders. Unfortunately, antipsychotics can cause side effects. One of the most common and serious is weight gain. People with schizophrenia are twice as likely to be obese than people in the general population.[1] Antipsychotic medication contributes to this. Other causes of overweight include physical inactivity, an unhealthy diet, other medications and the effect of some symptoms of mental illness. For example, depressed mood and lack of drive can make a person less active and contribute to weight gain. Overweight increases the risk of having a heart attack and stroke and developing many physical illnesses including high blood pressure, type 2 diabetes, sleep apnoea, osteoarthritis and some cancers. In general, the more overweight a person is, the greater their risk of developing these problems. 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.

Risk of weight gain with different antipsychotics

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.2 Antipsychotics differ in their risk of causing weight gain, and other side effects, but do not differ in their effectiveness in treating symptoms of schizophrenia or mania. 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.g. hearing voices) have not responded to treatment with at least two different antipsychotics.

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.

Table: Risk of weight gain with antipsychotics (table adapted from BAP ‘Guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment’[2])
Antipsychotic Risk of weight gain
Olanzapine High
Clozapine High
Chlorpromazine High/medium
Quetiapine Medium
Risperidone Medium
Paliperidone Medium
Asenapine Low
Amisulpride Low
Aripiprazole Low
Lurasidone Low
Ziprasidone Low
Haloperidol Low

Starting antipsychotics for the first time

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. In a study of people early in the course of schizophrenia, who received treatment for up to one year, approximately eight out of ten people prescribed olanzapine developed significant weight gain (defined as an increase of 7% or more of their starting weight).[3] This compared to about five or six out of ten people who gained significant weight when treated with quetiapine or risperidone. In a different study of people who had previously received long-term antipsychotics, and were followed for 18 months, significant weight gain (more than 7% of starting weight) occurred in one third of people who started olanzapine with rates about half of this for those starting quetiapine or risperidone.[4] Comparing the two studies shows that weight gain is more likely in people earlier on in their illness. This corresponds to people being treated by early intervention teams in the UK.

How antipsychotics cause weight gain

Weight gain is the result of taking in more energy (calories) from food and drink than are used up through the body’s resting metabolism plus activity and exercise. 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. Currently doctors and patients choose drugs partly based on their ‘average’ effects seen in clinical trials, for example the risk of weight gain as summarised in the table. In the future, it may be possible to conduct a simple blood test (i.e. a genetic screen) to identify a person’s likelihood to gain weight, and to develop other side effects, when treated with different drugs, so called personalised medicine. This could help people choose the best drug for their treatment. However, such a test is not currently available.

Managing weight gain with antipsychotics

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:

  1. Ensure that the risk of weight gain, and other side effects, are considered when choosing an antipsychotic. Wherever possible use drugs with a lower risk of weight gain.
  2. Monitor weight and Body Mass Index (BMI) during antipsychotic treatment. More regular measurements are needed in the first few months of treatment as this is when the risk of weight gain is highest.
  3. Use lifestyle approaches to manage weight gain. These include increased physical activity, exercise and changes to diet and eating behaviours, for example eating regular meals, having smaller portions and cutting down on foods and drinks rich in sugar and fat.
  4. If weight gain with an antipsychotic is problematic, consider switching to an antipsychotic with a lower risk of weight gain. Depending on the drugs involved, this can lead to weight loss. The risks of switching include the new medication causing side effects and being less effective for that person, leading to a relapse of their psychiatric disorder.

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.e. heart disease and stroke) in people with psychosis.2

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.[5]

Recent and ongoing research

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.[6] An additional advantage is that these programmes can reduce lipid (fat) and glucose (sugar) levels in the blood. These interventions can be given to individuals or to groups or both approaches can be combined. A recent example of a group intervention is the STRIDE study in the United States.[7] In STRIDE, people who were overweight, had a serious psychiatric illness and were taking an antipsychotic were randomised to weekly two-hour group meetings for six months or to normal care alone i.e. a control group. Participants were encouraged to eat a healthier diet and spend at least 25 minutes per day doing moderate activity. At six months, 40% of participants (compared with 17% of controls) had lost at least 5% of their initial body weight and 18% of participants (compared to 5% of controls) had lost at least 10% of their initial weight. It is generally accepted that for people who are overweight, losing 5% to 10% of total weight has health benefits[8], though greater weight loss is more beneficial. The intervention in STRIDE was also effective in reducing weight and lowering blood sugar levels at 1 year i.e. after an additional 6-month follow-up period. The STEPWISE study is currently assessing the effectiveness of a group programme to reduce weight in people with psychosis taking antipsychotics across ten mental health NHS trusts in England.[9]

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.e. staying on the current antipsychotic dose).[10] Within the dose reduction group, it is envisaged that some people will eventually stop medication whereas others will stabilize on a lower dose. The main outcomes in the RADAR trial are social functioning and relapse.

There is strong evidence that adding cognitive behaviour treatment (CBT), a ‘talking treatment’, to antipsychotic medication reduces symptoms of schizophrenia further and decreases the likelihood of rehospitalisation.5 Researchers have started investigating CBT as an alternative to antipsychotic medication to treat psychosis. 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.[11] CBT without antipsychotic medication, if proven to be effective, would not be suitable for everyone with psychosis. Nevertheless, it would widen treatment choice for some people and represent a major step forward in treating psychosis.

Summary

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.

Further information

Body Mass Index: The best way to determine whether weight is ‘normal’, or should be regarded as overweight and unhealthy, is to calculate the Body Mass Index (BMI) using a person’s height and weight. An NHS online BMI calculator is available at: www.nhs.uk/Tools/Pages/Healthyweightcalculator.aspx

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.bap.org.uk/pdfs/BAP_Guidelines-Metabolic.pdf

An article reviewing these Guidelines is available at: www.bap.org.uk/articles/bap-guidelines-metabolic/

References

[1] De Hert M et al (2009). Cardiovascular disease and diabetes in people with severe mental illness position statement from the European Psychiatric Association (EPA), supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC). Eur Psychiatry 24(6):412-24.

[2] Cooper SJ et al (2016). BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment.  J Psychopharmacol 30(8):717-48.

[3] McEvoy JP et al (2007). Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison. Am J Psychiatry 164(7):1050-60.

[4] Lieberman JA et al (2005). Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. N Engl J Med 353:1209-1223

[5] National Institute of Health and Care Excellence (NICE) (2014). Clinical guideline [CG178] Psychosis and schizophrenia in adults: Treatment and management [CG178]. Last updated: March 2014.

[6] Bruins J et al (2014). The Effects of Lifestyle Interventions on (Long-Term) Weight Management, Cardiometabolic Risk and Depressive Symptoms in People with Psychotic Disorders: A Meta-Analysis. PLoS One 9(12): e112276.

[7] Green CA et al (2015). The STRIDE weight loss and lifestyle intervention for individuals taking antipsychotic medications: a randomized trial. Am J Psychiatry 172(1):71-81.

[8] Wing RR et al (2011). Benefits of Modest Weight Loss in Improving Cardiovascular Risk Factors in Overweight and Obese Individuals with Type 2 Diabetes. Diabetes Care 34(7): 1481–1486.

[9] Gossage-Worrall R et al (2016). STEPWISE – STructured lifestyle Education for People WIth SchizophrEnia: a study protocol for a randomised controlled trial. Trials 17:475

[10] Registration information for the RADAR trial is available here

[11] Morrison AP et al (2014). Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial. The Lancet 383(9926), 1395-1403.

2 thoughts on “Antipsychotic medication and weight gain

  1. My Sons weight more than doubled in the 5 years that he took Clozapine. He recently passed away and complications of obesity is noted on his death certificate. So much more work is needed in the control of weight gain in these poor souls who are already suffering enough

    1. I’m very sorry to hear about your son. Clozapine can sometimes help when standard antipsychotic medications haven’t worked, particularly in treating distressing psychotic symptoms. It’s very unfortunate that clozapine can also cause serious side effects. I agree with you that more work is needed to manage weight gain associated with antipsychotics. The recent ‘BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment’ are one endeavour to help with this.

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