Olanzapine/DMO may trigger metabolic syndrome in schizophrenia patients

By Marilynn Larkin

NEW YORK (Reuters Health) - Monitoring plasma levels of olanzapine and N-desmethyl-olanzapine (DMO) may help avoid metabolic side effects in patients with schizophrenia, researchers in Taiwan suggest.

A previous study by Dr. Tzu-Hua Wu and colleagues at Tapai Medical University showed that olanzapine plasma concentrations of at least 22.77 ng/mL positively predicted efficacy of the drug in patients with schizophrenia. However, the relationship between plasma concentrations and metabolic disturbance are unclear, according to the authors.

To investigate, the team studied 151 patients (mean age, 41) diagnosed with schizophrenia whose mean dose of olanzapine was 14.2 mg. The mean plasma concentration of olanzapine was 37.0 ng/mL, and of DMO, 6.9 ng/mL. The mean concentration-to-dose (C/D) ratios were 2.9 ng/mL/mg for olanzapine and 0.6 ng/mL/mg for DMO; the mean ratio for OLZ/DMO was 7.0.

According to modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asians, at least three of the following are required for a diagnosis of metabolic syndrome: (1) waist circumference >90 cm in men or >80 cm in women; (2) fasting triglyceride levels of 150 mg/dL or higher; (3) fasting HDL-C levels <40 mg/dL in men or <50 mg/dL in women; (4) blood pressure 130/85 mm Hg or higher; and (5) fasting plasma glucose levels of 100 mg/dL or higher.

In this cohort, the average waist circumference was 88 cm; mean triglycerides, 150 mg/dL; HDL cholesterol, 48 mg/dL; blood pressure, 120/75; and blood glucose, 94 mg/dL.

The team tested both absolute drug levels and C/D ratios for their correlations to metabolic parameters.

As reported in Schizophrenia Research, online July 15, the total DMO C/D ratio negatively correlated with weight, body mass index, waist circumference, and C-peptide level. Further analyses determined that DMO concentrations >5.63 ng/mL and a DMO C/D ratio >0.35 ng/mL/mg were negative predictors of metabolic syndrome.

By contrast, an OLZ/DMO ratio >6.03 was found to be a positive predictor of metabolic syndrome.

Taken together with results from the team’s previous study, they suggest that optimal olanzapine therapy should maintain an OLZ/DMO CD ratio between 3 and 6 to maximize clinical efficacy and minimize metabolic side effects.

“Our findings suggested that therapeutic drug monitoring on olanzapine and DMO is a valuable tool to monitor metabolic side effects in olanzapine-treated patients with schizophrenia,” the authors conclude.

Dr. Jeffrey Lieberman, chairman of psychiatry at Columbia University College of Physicians and Surgeons in New York City, said the study is “a good attempt to develop pharmacokinetic correlations with therapeutic response and side effects, and define precisely the ‘therapeutic index’ for use of olanzapine.”

He had many questions about the methods and the results, however.

For example, he told Reuters Health by email, “their conclusion that DMO may inhibit the metabolic effects of olanzapine is unproven and implausible unless they have some pharmacologic evidence demonstrating this. The more likely interpretation is that fast metabolizers produce higher DMO concentrations while lowering olanzapine, which causes the metabolic side effects.”

“If these questions were satisfactorily answered,” Dr. Lieberman said, “then the measurement of blood levels of parent compound and metabolite could be standard practice as it would only require a blood sample. However, without additional information this cannot yet be implemented.”

Dr. Bruce Schwartz, Clinical Director of the Psychiatry and Behavioral Sciences at Montefiore Health System and Albert Einstein College of Medicine in New York City said, “Olanzapine has many metabolic effects, more than most of the other agents we use, and is not more effective at treating the symptoms associated with schizophrenia. I rarely use olanzapine as a first line drug because of (this).”

“Metabolic abnormalities occur with all the second generation antipsychotics,” he told Reuters Health by email. “Some are worse, like olanzapine or quetiapine - clozapine as well, but its effectiveness is markedly superior to other agents.”

“These agents are often routinely used as maintenance agents in the treatment of mood disorders, especially bipolar illness, and thus expose patients to metabolic syndrome,” he added. “We have better agents in bipolar, especially lithium carbonate, which is probably not used as often as it should be.”

Dr. Wu did not respond to requests for a comment.

SOURCE: http://bit.ly/2u6aPUk

Schizophr Res 2017.

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