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In schizophrenia, which antipsychotics cause the most weight gain, cholesterol, or glucose increases? Which antipsychotics cause the least? While a new study may not change your list much, there are some surprises here; for example, clozapine might have the lowest mortality.
Which antipsychotics are most likely to increase weight, cholesterol, and glucose? Are there any that do not cause these metabolic changes?
We will look at a new meta-analysis of antipsychotics in the treatment of schizophrenia from the same research group that looked at the relative efficacy of antipsychotics for schizophrenia. Now, they looked at relative metabolic effects comparing 18 different antipsychotics, including all of the second-generation antipsychotics and haloperidol.
Clozapine was the worst, followed by olanzapine, quetiapine, and risperidone, which was perhaps a tad better. Moreover, it was the same ranking for cholesterol and glucose increases. For all the rest, the authors caution that confidence in the ranking order was not strong. Ziprasidone was down there with placebo, and so was aripiprazole, but there is an artifact to consider. These metabolic studies often switched patients from a problematic medication, like olanzapine, to a different one. There were often reductions in weight and cholesterol, but these decreases were not entirely due to the different medications. Some of that reduction was due to getting off of the previous antipsychotic.
Furthermore, another problem: The average duration of the 100 randomized trials that these authors examined was 6 weeks. It would be good to see studies over 6 months’ duration. I cannot entirely agree with the authors’ list of medications with fewer metabolic effects. They named aripiprazole, ziprasidone, and the newest and more expensive: Brexpiprazole, cariprazine, and lurasidone. However, we know that the manufacturers tried hard to design studies to show that their medication causes less weight gain than other antipsychotics. Because, after all, if efficacy is not going to be better, why else would we switch from the inexpensive medications with which we have much more experience? So, we need to view these results that favor the new medications with great caution.
Nevertheless, of additional interest here, the authors have this network meta-analysis that showed that getting better was associated with getting fatter.
In other words, symptom improvement was associated with weight gain, cholesterol, and glucose increases. So, is there some direct connection between efficacy and metabolic consequences? Can you get better without gaining weight?
The authors conclude we do not know enough about mechanisms to speculate here. However, in their discussion, the authors, Toby Pillinger and colleagues in Lancet Psychiatry, make the obvious case for concern: Weight gain and cholesterol increases are cardiovascular risk factors.
I was struck when they cited a study that found that antipsychotic use is associated with decreased cardiovascular risk. Let’s take a quick look at that study. Drs. Jari Tiihonen and colleagues took advantage of the national registries of diagnoses, prescriptions, and Finland’s mortality.
They looked at everyone with a schizophrenia diagnosis who died between 1996 and 2006 and examined mortality rates for people taking antipsychotics vs no antipsychotics at all. Overall, the risk of dying was lower for people who took antipsychotics—and the more years the medications were taken, the lower the risk of dying. Perhaps that is not surprising because even though there are many ways to treat schizophrenia, not just antipsychotics, you might expect that overall outcomes would be better with the medications. However, there were some exciting twists. For example, which particular antipsychotic has the lowest mortality rate? It is clozapine. However, wouldn’t clozapine be the worst in terms of mortality due to metabolic risks?
Well, there is one other thing that separates clozapine from all the other antipsychotics; it is the one that lowers suicide rates. Moreover, in the Tiihonen study, you can see this effect driving down overall mortality among clozapine patients. Nevertheless, just looking at death from ischemic heart disease in that study, clozapine was not worse than taking nothing. In fact, for all the antipsychotics, cardiac mortality was not higher than for those taking nothing. Mortality for everyone with schizophrenia is high, whether they are taking antipsychotics or not. People die at least 10 years younger than those who do not have schizophrenia. However, from the Tiihonen data, it does not appear that increased cardiac mortality due to antipsychotics causes increased mortality in schizophrenia.
Of course, there are more than cardiovascular risks alone to consider [in] antipsychotic-associated weight gain. There are diabetes, its sequelae, worsening of orthopedic problems, and even increased susceptibility to other medical problems, like just lately, COVID-19.
In conclusion, for schizophrenia, Drs. Pillinger and colleagues have rank ordered antipsychotics by metabolic risk. They name aripiprazole and ziprasidone as worthy of particular consideration, as well as brexpiprazole, cariprazine, and lurasidone. For more from this new meta-analysis, which is linked here, look at Figures 4 and 5, where the authors go beyond rank order to look at some more prominent picture relationships between metabolic parameters and outcomes.
Abstract
Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis
Toby Pillinger, Robert A McCutcheon, Luke Vano, Yuya Mizuno, Atheeshaan Arumuham, Guy Hindley, Katherine Beck, Sridhar Natesan, Orestis Efthimiou, Andrea Cipriani, Oliver D Howes
Background: Antipsychotic treatment is associated with metabolic disturbance. However, the degree to which metabolic alterations occur in treatment with different antipsychotics is unclear. Predictors of metabolic dysregulation are poorly understood and the association between metabolic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the basis of their metabolic side-effects, identify physiological and demographic predictors of antipsychotic-induced metabolic dysregulation, and investigate the relationship between change in psychotic symptoms and change in metabolic parameters with antipsychotic treatment.
Methods: We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included blinded, randomised controlled trials comparing 18 antipsychotics and placebo in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in body weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships between metabolic change and age, sex, ethnicity, baseline weight, and baseline metabolic parameter level. We examined the association between metabolic change and psychopathology change by estimating the correlation between symptom severity change and metabolic parameter change.
Findings: Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with placebo ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m2 (-0·68 to 0·17) for haloperidol to 1·07 kg/m2 (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for brexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for brexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted by higher baseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p<0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035).
Interpretation: Marked differences exist between antipsychotics in terms of metabolic side-effects, with olanzapine and clozapine exhibiting the worst profiles and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign profiles. Increased baseline weight, male sex, and non-white ethnicity are predictors of susceptibility to antipsychotic-induced metabolic change, and improvements in psychopathology are associated with metabolic disturbance. Treatment guidelines should be updated to reflect our findings. However, the choice of antipsychotic should be made on an individual basis, considering the clinical circumstances and preferences of patients, carers, and clinicians.
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Reference
Pillinger, T., McCutcheon, R. A., Vano, L., Mizuno, Y., Arumuham, A., Hindley, G., Beck, K., Natesan, S., Efthimiou, O., Cipriani, A., & Howes, O. D. (2020). Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: A systematic review and network meta-analysis. The Lancet Psychiatry, 7(1), 64-77.
Related References
Tiihonen, J., Lönnqvist, J., Wahlbeck, K., Klaukka, T., Niskanen, L., Tanskanen, A., & Haukka, J. (2009). 11-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study). The Lancet, 374(9690), 620-627.
