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This Quick Take looks at a clinic using their own data to examine which of the newer antipsychotics cause more weight gain than others. But first, some crucial context.
Hi! Jim Phelps here for the Psychopharmacology Institute. As you know, antipsychotics cause weight gain, and weight gain commonly leads to a constellation of symptoms called metabolic syndrome—abdominal obesity, high triglycerides, low HDLs, and high blood pressure. Underlying that syndrome is a physiologic shift of increasing insulin resistance. If that goes on for a while, one can finally see the other symptom in that constellation—increased blood glucose. In other words, elevated glucose is a very late manifestation of metabolic syndrome. We should go on alert when we see any of the other ones—abdominal obesity, high triglycerides, low HDLs, and high blood pressure.
So, our medications cause weight gain, and weight gain can cause insulin resistance. That’s distressing but not really news, is it? What’s new is the series of findings from Dr. Cynthia Calkin and colleagues at Dalhousie University showing that insulin resistance worsens the course of bipolar disorders. Got that? The insulin resistance that we can increase by causing weight gain can make the very thing we’re trying to treat harder to treat. As a dramatic example of this mechanism in action, Dr. Calkin and her colleagues showed that treating insulin resistance with metformin improved the course of bipolar disorder. We should know which of our antipsychotics are the worst in terms of causing weight gain and which are the least concerning.
To answer that question from their own experience, a large private outpatient clinic with multiple psychiatric providers looked at their own records and quantified 6-month and 1-year weight gain for some of the newer antipsychotics. For lurasidone vs olanzapine, for example, they have about 400 patients in each group. For the other new antipsychotics, far fewer. Patients were not randomized, and some of them who went on lurasidone might just have been on olanzapine or some other substantial weight gainer. So, taking all that into account, let’s look at the numbers. The results were: Olanzapine patients gained on average 10 pounds in a year. Lurasidone patients, zero.
Now, the authors emphasized that this doesn’t mean that lurasidone doesn’t cause weight gain. They’re just reporting what happened to their patients’ weight in 1 year. The patients’ diagnoses were almost entirely mood disorders. A few were diagnosed with PTSD, and only a handful of patients were diagnosed with schizophrenia.
What about newer antipsychotics? Sample sizes were 35 for cariprazine and 60 to 70 for iloperidone, brexpiprazole, and asenapine. Less robust data there than for lurasidone and olanzapine. The cariprazine group showed a small weight loss at 6 weeks and then a 4-pound average gain at 1 year. Iloperidone and brexpiprazole, 5- and 6-pound weight gains at 1 year, respectively. Of course, for comparison, it would be useful to know the average yearly weight gain in upstate New York, where these clinics are located.
To cite a study from 1993, the average yearly weight gain amongst U.S. adults per year is 1 to 2 pounds. In contrast, a 2021 Harris Poll for the American Psychological Association found that in the past year of the COVID-19 pandemic, the median weight gain was 15 pounds, and among 42% of respondents who said they gained more weight than intended, the average increase was 29 pounds.
We should do everything we can to avoid adding any more weight to this problem. But does that include switching from a generic atypical to an expensive one like lurasidone? For comparison, look at the 1-year weight gain on perphenazine, once regarded as among the best of the first-generation antipsychotics. In the 1.5-year CATIE study, the net weight change on perphenazine was a loss of 2 pounds, while the olanzapine group gained 9.5 pounds. Now, perphenazine carries a higher risk of tardive dyskinesia than lurasidone, and like other second-generation antipsychotics, lurasidone likely has more direct antidepressant effects enough to cause hypomania and mixed states in some of my patients. But if all you need is an antimanic or an antipsychotic effect, might perphenazine be a candidate at about $25 a month compared to lurasidone at $1300 or higher?
Over 1 year, lurasidone caused no weight gain at all on average in this patient population, while olanzapine caused a gain of 10 pounds. Other new antipsychotics were intermediate in terms of weight gain. Again, this was in patients with mostly mood disorders in a private outpatient clinic. For more on this, I think Dr. Calkin’s paper on insulin resistance and the outcomes in bipolar disorder is the most important reference here. If we are worsening the very thing we’re trying to improve, surely that warrants our attention.
Abstract
Comparison of the Metabolic Characteristics of Newer Second Generation Antipsychotics: Brexpiprazole, Lurasidone, Asenapine, Cariprazine, and Iloperidone with Olanzapine as a Comparator
Jessica Greger, Traci Aladeen, Emily Lewandowski, Rachael Wojcik, Erica Westphal, Michelle Rainka, Horacio Capote
Purpose/Background: Extensive research has been conducted comparing the metabolic characteristics of older second-generation antipsychotics (SGAs); minimal data exist comparing the long-term metabolic effects of SGAs approved in the last 10 years.
Methods/Procedures: A retrospective chart review of patients treated with brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone (newer SGAs) for at least 6 weeks at an outpatient psychiatric practice was conducted. Patients treated with olanzapine, an older SGA, were included as a comparator. Metabolic characteristics were collected at baseline, approximately 6 weeks, 12 weeks, and for up to 12 months.
Findings/Results: Of the newer SGAs, there were statistically significant increases in patients’ average weight at 12 weeks and 1 year or less with brexpiprazole (2.48 lb, P = 0.02; 5.97 lb, P = 0.01) and iloperidone (4.54 lb, P < 0.01; 5.13 lb, P = 0.02). Brexpiprazole and iloperidone resulted in significant increases in body mass index, up to a 0.90-kg/m2 average increase in patients taking brexpiprazole at 1 year or less. Minimal weight gain was seen with cariprazine (4.25 lb, P = 0.42) and asenapine (1.80 lb, P = 0.62) at 1 year or less after treatment initiation. Although not statistically significant, lurasidone showed an average weight loss of up to 0.60 lb at 1 year or less (P = 0.56).
Implications/Conclusions: Although some weight gain was seen with the newer SGAs, all demonstrated significantly favorable metabolic characteristics compared with olanzapine. Monitoring of weight and metabolic parameters remain important in patients treated with SGAs.
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Reference
Greger, J., Aladeen, T., Lewandowski, E., Wojcik, R., Westphal, E., Rainka, M., & Capote, H. (2021). Comparison of the metabolic characteristics of newer second generation antipsychotics: brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone with olanzapine as a comparator. Journal of Clinical Psychopharmacology, 41(1), 5-12.
Related References
- Calkin, C. V., Ruzickova, M., Uher, R., Hajek, T., Slaney, C. M., Garnham, J. S., … & Alda, M. (2015). Insulin resistance and outcome in bipolar disorder. The British Journal of Psychiatry, 206(1), 52-57.
- Calkin, C. Adjunctive metformin for treatment refractory depression in bipolar disorder. Presented at the International Society for Bipolar Disorders meeting, May 2021.
- Greger, J., Aladeen, T., Lewandowski, E., Wojcik, R., Westphal, E., Rainka, M., & Capote, H. (2021). Comparison of the metabolic characteristics of newer second generation antipsychotics: brexpiprazole, lurasidone, asenapine, cariprazine, and iloperidone with olanzapine as a comparator. Journal of Clinical Psychopharmacology, 41(1), 5-12.
- Hutfless, S., Maruthur, N. M., Wilson, R. F., Gudzune, K. A., Brown, R., Lau, B., Fawole, O. A., Chaudhry, Z. W., Anderson, C., & Segal, J. B. (2013). Strategies to Prevent Weight Gain Among Adults. Agency for Healthcare Research and Quality (US).
- American Psychological Association. One year later, a new wave of pandemic health concerns https://www.apa.org/news/press/releases/stress/2021/one-year-pandemic-stress
