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Authors of a large meta-analysis identified antipsychotic medications with the strongest metabolic effects, which often were also the ones with the greatest efficacy.

Not surprisingly, clozapine (Clozaril) and olanzapine (Zyprexa) were associated with the largest degree of metabolic dysregulation across virtually all variables, whereas aripiprazole (Abilify), brexpiprazole (Rexulti), cariprazine (Vraylar), lurasidone (Latuda), and ziprasidone (Geodon) were the safest in this regard, reported Toby Pillinger, PhD, of King's College London, and colleagues.

However, certain medications were associated with different adverse metabolic effects such that, for example, risperidone (Risperdal) and paliperidone (Invega) were linked with weight gain but not increased fasting blood glucose, the researchers wrote in their study online in .

"Interestingly, some of the drugs were shown to perform better than placebo on some metabolic measures: for instance, when compared with placebo, lurasidone led to reductions in glucose, cariprazine to reductions in LDL [low-density lipoprotein] cholesterol, and aripiprazole and brexpiprazole to increases in HDL [high-density lipoprotein] cholesterol," the researchers said.

Moreover, the degree to which symptom severity improved was associated with increased metabolic dysregulation in terms of body weight, body mass index (BMI), total cholesterol, LDL cholesterol, and HDL cholesterol, "suggesting that the most efficacious antipsychotics are associated with the greatest metabolic disturbance," Pillinger and colleagues said.

"Our findings do not mean that metabolic disturbance is a requirement for efficacy, but do highlight that those drugs that are most efficacious tend to have the broadest pharmacology, and metabolic effects might be due to off-target actions," the researchers explained.

This correlation between symptom improvement and metabolic adverse effects could be a result of patients taking their medication more consistently, wrote Yoav Domany, MD, of Sheba Medical Center, and Mark Weiser, MD, of Tel Aviv University, both in Israel, in an .

Alternatively, it could be that certain neurotransmitters involved with metabolism -- such as serotonergic, histaminergic, and muscarinic agents -- work together with D2 dopamine receptor blockade, resulting in improvement, Domany and Weiser added.

They said that notably, fasting glucose increased more in patients with higher versus lower baseline weight, a signal that would discourage treating patients with obesity with olanzapine and clozapine and that contrasts with findings from prior research.

These discrepancies may be due to the large sample size in this meta-analysis, or the fact that the researchers restricted the analysis to trials evaluating acute treatment, whereas prior studies have measured weight gain in time periods as long as 3 years, Pillinger and co-authors explained.

Domany and Weiser said the analysis can help inform a personalized medicine approach in treating patients with schizophrenia, but the research was limited by a median treatment duration of just 6 weeks in the included studies, whereas most patients will receive chronic treatment.

"Future research should attempt to identify genetic characteristics associated with efficacy and adverse effects to facilitate personalized psychiatry," the editorialists wrote.

Study Details

The analysis involved 100 blinded, randomized controlled trials evaluating 18 antipsychotics for the treatment of schizophrenia.

The studies included a total of 25,952 mostly white participants (64%), who were a mean age of 35 years. The risk of bias was identified as "high" for 16% of the trials, and an additional 16% of trials showed no evidence of bias, the authors reported.

Higher baseline body weight (P=0.0015), male sex (P=0.0082), and non-white ethnicity (P=0.040) were all risk factors for metabolic adverse events, "suggesting an overlap between risk factors for metabolic disease in the general population and in people with antipsychotic-induced metabolic disease," the researchers noted.

In terms of mean weight gain, haloperidol (Haldol) was ranked the best (-0.23 kg) and clozapine the worst (3.01 kg). For BMI increase, haloperidol was also the best (-0.25 points) and olanzapine was the worst (1.07). Lurasidone was best for glucose changes (-5.23 mg/dL) and clozapine was worst (18.92 mg/dL).

LDL cholesterol changes were worst in patients treated with olanzapine (7.72 mg/dL) and best in those treated with cariprazine (-5.02 mg/dL). Total cholesterol was poorest in patients on clozapine (-3.48 mg/dL) and best for patients on cariprazine (21.62 mg/dL), and HDL cholesterol changes were worst in patients on brexpiprazole (1.93 mg/dL) and best for patients on amisulpride (-3.86 mg/dL). Finally, triglyceride levels were poorest with clozapine (86.73 mg/dL) and best with brexpiprazole (-0.88 mg/dL).

Pillinger and colleagues calculated that based on this analysis, 6 weeks of treatment with olanzapine and clozapine would increase body weight by about 3 kg, BMI by one point, and triglycerides by 88.5 mg/dL, which could have significant cardiovascular effects.

"At the onset of psychotic illness and before antipsychotic prescription, patients with schizophrenia have impaired glucose and lipid regulation," the team wrote. "Thus, certain antipsychotics, within a few weeks, might worsen metabolic homeostasis in an already susceptible cohort, which reinforces international recommendations that metabolic monitoring should accompany antipsychotic prescription."

Study limitations, the researchers said, included that the analysis primarily looked at newer-generation antipsychotics because data on metabolic parameters was not available for most of the studies conducted more than 15 years ago. In addition, lifestyle factors that could have affected metabolic parameters were not measured.

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