The lead author of the study, Roger S. McIntyre, Associate Professor of Psychiatry and Pharmacology at the University of Toronto, indicated that while the findings could be related to a need for higher doses in people with higher body mass indexes, it could also be that these differences in body mass and blood sugar could reduce the effectiveness of the drug at any dose. While this type of study is apparently uncommon in psychiatric research, it is actually quite important in helping us understand patterns of effectiveness in various medications used to treat bipolar disorder.

Traditionally, studies have looked at groups of patients and how they respond to medicines without any kind of stratification along these lines. Research studies often look at how factors such as substance use, other diagnoses, age, and sex contribute to medication effects. But we haven’t routinely looked at obesity and hyperglycemia, which are common conditions, and how they might affect medication response – positive or negative.

Paradoxically, ziprasidone is often chosen specifically for patients who are already overweight because it doesn’t have the same problems with weight gain and changes in glucose metabolism as the other atypical antipsychotics. If this is the same population that tends to have a less complete response to ziprasidone, then this could affect the medication choices doctors make when treating acute mania.

Furthermore, while this study looked at ziprasidone, it makes sense to do similar studies with the other atypical antipsychotics. Most of them cause weight gain and increase risk of problems with blood sugar. Now we must consider the possibility that those very side effects may reduce the effectiveness of the medicines themselves. This further complicates an already complex picture of the risks and benefits of atypical antipsychotics.

Photo by Tony Alter, available under a Creative Commons attribution license.

The study found that:

• Children and adolescents with major depressive disorder may be at increased risk for developing obesity.
• Patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity. (Abdominal obesity is specifically related to higher risk of cardiovascular disease.)
• Persons living with obesity who seek weight-loss treatment may have elevated rates of depressive and bipolar disorders.
• Obesity is associated with major depressive disorder in females.
• Abdominal obesity may be associated with depressive symptoms in females and males.
• Most overweight and obese persons do not have mood disorders.

The study suggests an overlap between mood disorders and obesity, but does not prove a cause – effect relationship in either direction. Obesity and mood disorders are complex disorders that are caused by the interaction of many biological and environmental conditions – it is not a simple relationship between the two conditions – but the study suggests important interactions that need to be better understood.

Understanding the Complexity of Contributing Factors

What we do know is that numerous complex factors contribute to the growing epidemic of obesity, and we understand that it’s not just a problem of willpower or as simple as “eat less, exercise more.” Highly interconnected and deeply rooted neural pathways affect eating, appetite, satiety, and body composition in ways we are just starting to comprehend.

We also know that a number of medications used to treat depression and bipolar disorder compound the problem by creating significant weight gain which may worsen previously existing obesity. In addition, for people with bipolar disorder and obesity, the levels of suffering layer on top of one another and exacerbate each other.

Until we find effective treatments for the underlying cause(s), we must work toward treating the symptoms – in this case, obesity – without aggravating the mania or depression. While diet, exercise, and medication adjustments may be effective for mild to moderate weight gain, these options are not always effective in treating obesity or they may raise the risk of triggering a switch to mania.

Bariatric (Weight Loss) Surgery

Bariatric (weight loss) surgery has become an increasingly prescribed option for people whose obesity has not responded to other interventions. It can make a dramatic difference in people’s health and wellbeing. (Of course, any surgical procedure carries some risk, as well.)

I have had several patients in my practice with bipolar disorder who have had some type of bariatric surgery. They have all lost weight, and it has helped their self-esteem, health, and energy. Getting the surgery approved was somewhat of a struggle, though, because of concerns that people with bipolar disorder might not have good outcomes.

Studies Supporting Bariatric Surgery for Obesity in Bipolar

A study published last month looked at this very question and the results are similar to my clinical experiences. (Obesity Surgery, 2011 Mar 6. [Epub ahead of print] “Bariatric Surgery: 1-Year Weight Loss Outcomes in Patients with Bipolar and Other Psychiatric Disorders.” Steinmann WC, Suttmoeller K, Chitima-Matsiga R, Nagam N, Suttmoeller NR, Halstenson NA.) They retrospectively compared groups of people with bipolar disorder, other psychiatric disorders, and no psychiatric diagnosis and found that all groups did well – with substantial weight loss and no increased rates of negative outcomes.

Another recent study entitled “Surgical treatment of morbid obesity among patients with bipolar disorder: a research agenda,” (Advances in Therapy, Apr 2011, Ahmed AT, Blair TR, McIntyre RS) concludes:

The considerable hazards posed by obesity in BD, as measured by illness complexity and premature mortality, provide the basis for hypothesizing that bariatric surgery may prevent and improve morbidity in this patient population. In addition to physical health benefits, bariatric surgery may exert a robust and favorable effect on the course and outcome of BD and reduce obesity-associated morbidity, the most frequent cause of premature mortality in this patient population.

Looking Ahead to More Research

I was pleasantly surprised to see these articles, and I will use them as back-up in the future when I am asked to provide my opinion about whether my patient with bipolar disorder could safely undergo a weight loss procedure. Of course, some patients may not be stable enough for this procedure and some may pursue it out of poor judgment based on manic or depressive symptoms, so it is not a viable or recommended option in all cases. But it seems that it may be a reasonable option for those suffering with medically dangerous obesity and bipolar disorder.

I am curious to see any further studies examining psychiatric outcomes in people with bipolar disorder who undergo weight loss surgery. Plenty of questions remain to be answered, including whether the mental health of those who have the surgery is ultimately better, worse, or the same as those with bipolar and obesity who’ve elected not to have the surgery. This an interesting question. I will keep my eyes out for any studies that might be looking into this, and I will keep you posted.

Please share your experiences and insights. If you have had weight loss surgery and live with depression or bipolar disorder, are you satisfied with the results? If you lost weight as a result, did the weight loss improve your moods or your ability to maintain mood stability? Having been through it, do you have any tips or cautions to share with those who are considering it? Would you recommend it?

Photo by Cliff, available under a Creative Commons attribution license.

Atypical antipsychotics were designed primarily to treat schizophrenia but have proven effective in treating mania and mixed-manic episodes and in the maintenance treatment of bipolar disorder. They are generally very useful in treating psychotic “breaks” that may accompany severe manic episodes. The atypicals may also be helpful in treating depression. This post shines the light on Zyprexa (olanzapine) – the first atypical antipsychotic approved for the treatment of acute bipolar mania.

These medications are called “atypical” because they work a little differently than the older, standard antipsychotics, including Thorazine and Haldol. The older generation of medications carried risks of movement and muscle disorders that could be irreversible. The “second generation” group does not carry as high a risk of movement problems but carries its own set of risks that can be as difficult to manage. Several large recent studies have clearly indicated that the older medications are often equally effective to the newer ones and that the side-effect profiles, while different, are no better or worse in terms of patient satisfaction. In particular, the older medications do not typically cause weight gain, which is one of the biggest problems with the newer ones.

All antipsychotic medications work by blocking the neurotransmitter dopamine. The different medications do this to lesser or greater degrees and they also have differing effects on other transmitter systems, most notably serotonin. This group of medications is powerful and typically quite effective at eliminating psychosis (hallucinations and delusions, for example) and at reducing overall agitation and manic excitement. Some of the atypicals have an antidepressant effect as well, which can make them valuable in bipolar disorder.

People who don’t respond well to the first-tier bipolar medications, including lithium and Depakote, often respond well to one of the atypical antipsychotics – either alone or in tandem with other bipolar medications.

The side effects that can be seen with these medications include the following:

• Weight gain is the most prominent and unpleasant side effect of most of these medications.
• Increased risk of developing metabolic syndrome (pre-diabetes) and diabetes and problems with sugar metabolism.
• Increased cholesterol and other changes in fat and lipid metabolism.
• Movement problems like Parkinson’s disease (tremors and stiffness) (lower risk than older medications).
• Irreversible uncontrolled movements called tardive dyskinesia – facial twitches or uncontrolled movements of the tongue, lips, arms, or other body parts (lower risk than older medications).
• Akathisia – a feeling of extreme restlessness commonly described as the overwhelming desire to “jump out of your skin.”
• Changes in cardiac rhythms.
• Increases in the levels of the hormone prolactin – sometimes causing breast enlargement in men and lactation or menstrual problems in women.

The weight gain issue is the biggie for most people, especially in the case of Zyprexa. Some patients report gaining over 50 pounds in a matter of weeks, which can lead to other serious medical conditions, including diabetes. Of course, the weight gain also creates a host of other problems related to general well being and self image. Although diet and exercise may alleviate the weight gain for some people, these solutions are often unrealistic and place a further burden someone who’s already dealing with plenty of emotional pain and stigma. (See “Preventing and Reversing Weight Gain Associated with Psychiatric Medications.”)

Lilly offers Zyprexa in four formulations:

• Zyprexa IntraMuscular (for injection), which is used to treat extreme agitation – overexcited, hostile, or threatening behavior – in people with schizophrenia or bipolar disorder. This is usually used to treat acute mania and/or psychosis. Later, your doctor is likely to switch you to a different form of Zyprexa or a different medication altogether for long-term maintenance.
• Zyprexa oral – the most common type prescribed.
• Zydis – a melt in your mouth wafer version of Zyprexa.
• Symbyax – a combination of Prozac (fluoxetine) and Zyprexa (olanzapine), designed to treat both depression and mania.

If you’ve taken any form of Zyprexa for bipolar disorder or are a doctor who has prescribed it, please share your experiences, insights, and observations.

Doctors and therapists don’t always treat medication-induced weight gain with the sensitivity or importance it deserves. As long as you’re not manic or depressed, they seem to think you should be thankful and accept the weight gain as a necessary trade-off for the privilege of mood stability. Others casually shift the responsibility to their patients, suggesting that normal exercise and dieting can shed the unwanted pounds, rarely acknowledging the fact that when you’re depressed, you may not feel much like jogging or swimming laps.

When you’re not the one carrying the extra 10 to 50 pounds, it’s easy to shrug it off as though it’s of little concern, but weight gain can and often does lead to other problems:

• Poor self esteem – from tight-fitting clothes and looking or feeling not as fit as they would like.
• Medication noncompliance – stopping the medications they suspect of causing the weight gain.
• Physical health risks – including high-cholesterol, diabetes, and heart disease.

Weight gain is one of the most common and difficult side effects of many of the medications used to treat bipolar disorder and other psychiatric illness. It is something I address daily with patients and families – when picking an initial medication or adjusting or changing prescriptions. This topic comes up constantly.

In this post, I highlight the most common culprits (the medications most likely to cause the most weight gain) and offer a pro-active approach that has helped many of my patients keep the pounds off or shed them later.

Atypical Antipsychotics

Almost all of the atypical antipsychotics are notorious for causing fairly significant weight gain in most (but not all) people who take them. Here’s the list of culprits ranked from most to least risk for causing weight gain:

• High risk: Olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), aripiprazole (Abilify), and clozapin (Clozaril)
• Little to no risk: Ziprasidone (Geodon) and older first-generation antipsychotics such as perphenazine (Trilafon)

The weight gain from antipsychotics appears to come from increased appetite (“hyperphagia”) and some changes in metabolism. This family of medicines also has varying degrees of risk of certain health risks such as diabetes and elevated cholesterol, which may be related to the medication’s effect on metabolism.

Antidepressants and Antianxiety Medications

Antidepressants and antianxiety medications all have some risk of weight gain, although not typically in the same severe range as the antipsychotics. The risk seems to be more individualized – some people notice a lot of change in appetite and weight and some notice little. Occasionally, some people actually lose weight on these meds. In addition, these medications do not carry specifically the risks of diabetes and high cholesterol.

The most common antidepressants and antianxiety medications are the SSRI’s and SNRI’s (the weight gain risk really depends on the individual):

• SSRI’s: Fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram (Celexa) are some examples.
• SNRI’s: Venlafaxine (Effexor) and Duloxetine (Cymbalta) are the most common.

Bupropion (Wellbutrin), which is in a class of its own, is the only antidepressant without any risk of weight gain – but it is not particularly effective for anxiety.

Anti-Manics or “Mood Stabilizers” and Anti-Seizure Medications

Mood stabilizers and the anti-seizure medications often used to treat or prevent mania may also carry the risk of causing weight gain, but the risk varies depending on the medication and its effect on the person taking it:

• High risk: Valproic acid (Depakote)
• Moderate risk: Lithium
• Low risk: Lamotrigine (Lamictal) and carbemazapine (Tegretol)

Curbing Weight Gain via Medication

When medication triggers weight gain, one of the more obvious solutions is through medications – either selecting a different medication that’s less likely to cause weight gain or adding a medication that has a track record for negating the weight-gain side effect. Here are some common options:

• Choose a different medication. If Zyprexa causes significant weight gain, for example, switching to Geodon may deliver similar benefits with little or no risk of causing weight gain.
• Try a different form of the same medication. Olanzapine (Zyprexa), for example, is also offered as a dissolvable tablet (Zydis) that melts in your mouth. The theory is that your mouth membranes absorb most of the medication before it gets into your stomach where it’s more likely to stimulate the appetite. (This does not have any scientific support at the moment, but it doesn’t hurt to try.)
• Add topiramate (Topamax) to the mix. Topiramate has been shown, in some studies, to reduce appetite and limit weight gain (particularly weight gain associated with atypical antipsychotics).
• Add metformin (Glucophage) to the mix. Metformin, a medication used to treat diabetes, –is being studied to see if it may reduce weight gain and/or the risk of developing diabetes associated with some psychiatric medications.
• Replace your atypical antipsychotic with an older, first-generation antipsychotic. The atypical antipsychotics (second-generation antipsychotics) generally have been thought to have fewer serious side effects than the older versions. However, several recent studies have indicated that the atypical antipsychotics may not have any better outcomes than the older ones, such as perphenizine (Trilafon) and molindone (Moban). And while the older antipsychotics have their own particular risk profile – movement disorders in particular – they do not have the same weight gain and metabolic risks seen in the newer drugs. So it seems that the choices for medications may be broader than we have gotten used to recently. In other words, for some people, the older, less expensive antipsychotics may be a better choice.

In some cases, changing medications can be “just what the doctor ordered.”

Taking a Proactive Approach to Curbing Weight Gain

In my practice, we remain well aware of the potential weight gain risks associated with the various medications and prescribe medications in such a way as to reduce the risks as much as possible. In addition, we take a very proactive approach in monitoring weight and take action as soon as we notice any changes:

1. We monitor weight and appetite from the start, so that we can take action before the weight gain becomes a big problem. You needn’t jump on the scales every day. We just check weights at regular visits and sometimes recommend briefly keeping a food and/or appetite journal.
2. We order regular lab tests to keep an eye on glucose and cholesterol levels. The testing should be done at least once a year – probably more like every six months. It should include just a routine glucose and a lipid panel. The “range” on the lab slip shows the cut offs, but more importantly, we’re looking for significant shifts from baseline.
3. When starting a new medication or changing medications, work with your doctor to increase the calories you burn while maintaining your caloric intake. Any movement will do, so don’t think you have to join a gym – walking a little more each day can do wonders. Likewise, you don’t have to go on a strict diet – try to keep the calories going in about the same as before or with as little increase as possible. Some studies have shown that the weight gain can be more limited with a proactive approach to nutrition and exercise.We may include a consult with a nutritionist or exercise trainer (assuming that’s an option) to help plan and monitor calorie intake and develop reasonable and doable exercise or movement plans. Small, manageable changes are the goals.
4. We often work together with the primary care doctor in all of the steps. Because of the medical risks with the atypicals, it’s a good idea to keep the primary care physician in the loop; they can keep a closer eye on health issues related to these meds, and may have other ideas or input regarding keeping weight gain down to a dull roar.

The most important factor here is good communication with your prescriber and regular monitoring of the medications and their effects – both good and bad. Some weight gain may be unavoidable, but try to be honest with your doctor about what you will and will not live with in this department.

Remember: Call your doctor to discuss any problems with the medicines, rather than stopping the medication on your own. This is a team project, and the outcomes are better when the team works together.

If you have any additional tips or suggestions on preventing or reversing the weight gain associated with psychiatric medications, please share your insights and experiences with others by posting a comment.