Question explored with the scientific record
what happened with zyproxa from eli lili
The short version: olanzapine (Zyprexa) is a powerful drug that causes substantial weight gain and metabolic damage, and the evidence for this is unusually solid.
You asked what happened with Zyprexa. The answer is that a mountain of evidence, much of it from independent and government-funded studies, documented that Eli Lilly's drug causes rapid weight gain, insulin resistance, new-onset diabetes, and dangerous changes in blood lipids. This is not a rare side effect. It is a predictable, dose-dependent, and often severe metabolic injury that occurs in a large fraction of people who take the drug.
The evidence is unusually strong because it comes from multiple sources that agree. The CATIE trial, a large independent government-funded study, found that patients on olanzapine gained an average of 9.4 pounds over 18 months, with 30% gaining more than 7% of their body weight [3]. Cholesterol and triglycerides rose significantly, and HbA1c increased [3]. A VA database study of nearly 57,000 patients found that olanzapine carried a 15% higher risk of new diabetes compared to risperidone, with an attributable risk of 0.63% per year [1]. A study of antipsychotic-naive patients found that olanzapine significantly increased diabetes risk, with a median onset of 3.9 years after starting the drug [4]. A 2025 systematic review confirmed that glucose dysregulation often emerges within 6 to 12 months of starting olanzapine [5].
The mechanism is not subtle. Olanzapine increases food intake and resting energy expenditure, but the net effect is rapid weight gain [13]. It raises leptin levels within hours of the first dose [8]. It decreases ghrelin, the hunger-regulating hormone [12]. It increases insulin resistance directly, not just through weight gain [6]. In children and adolescents, a 27-day inpatient study found that olanzapine caused a mean BMI increase of 1.7 kg/m², with 28% of patients becoming overweight in less than a month [2].
The company responded by developing a combination pill with samidorphan, a drug intended to block the weight gain. Animal studies showed it worked in rats and monkeys [10]. Human trials showed it partially mitigated the weight gain, but the combination still caused significant metabolic changes [9]. Metformin has been studied as an add-on to prevent weight gain, with mixed results: some trials showed modest benefit [9, 11], others showed no significant difference [7].
The bottom line is that olanzapine's metabolic toxicity is not a disputed finding. It is one of the best-documented adverse drug effects in modern psychiatry. The drug works for severe mental illness, but the metabolic cost is high, predictable, and requires active monitoring and management.
My call: olanzapine causes substantial, well-documented metabolic harm including weight gain, diabetes, and dyslipidemia. The evidence for this is strong and consistent across multiple study designs and populations. Confidence: high.
Sources used 13
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Incidence of Newly Diagnosed Diabetes Attributable to Atypical Antipsychotic Medications
A retrospective VA cohort study estimated the incidence of new-onset diabetes and diabetic ketoacidosis among schizophrenia patients on stable antipsychotic monotherapy, and quantified drug-specific risks attributable to atypical antipsychotics.
DOI: 10.1176/appi.ajp.161.9.1709 -
Effects of Olanzapine and Risperidone on Metabolic Factors in Children and Adolescents: A Retrospective Evaluation
This study evaluates the metabolic effects of olanzapine and risperidone on children and adolescents in an inpatient psychiatric setting, finding significant increases in body mass index (BMI) and risk factors for diabetes and metabolic syndrome associated with olanzapine treatm…
DOI: 10.1097/01.pra.0000358319.81307.a5 -
Metabolic Findings From the CATIE Trial and Their Relation to Tolerability
Metabolic findings from the CATIE trial indicate high metabolic syndrome prevalence in schizophrenia, with olanzapine and other antipsychotics driving weight gain and dyslipidemia, impacting tolerability and necessitating routine metabolic monitoring.
DOI: 10.1017/s1092852900026663 -
Antipsychotics Associated with the Development of Type 2 Diabetes in Antipsychotic-Naïve Schizophrenia Patients
This study investigates the association between various antipsychotic medications and the development of type 2 diabetes in antipsychotic-naïve schizophrenia patients, revealing that olanzapine and mid-potency first-generation antipsychotics significantly increase diabetes risk,…
DOI: 10.1038/npp.2010.78 -
The Onset of Glucose Dysregulation Among Adults Treated with Antipsychotics: A Systematic Review of Cohort Studies
Systematic review of real-world cohort studies showing glucose dysregulation often emerges within 6–12 months after starting antipsychotics, especially clozapine and olanzapine, with structured inpatient care and proactive monitoring potentially mitigating risk and delaying prog…
DOI: 10.29103/jkkmm.v5i1.24735 -
Effects of Olanzapine and Risperidone on Glucose Metabolism and Insulin Sensitivity in Chronic Schizophrenic Patients With Long-Term Antipsychotic Treatment
In chronically treated inpatients with schizophrenia, a 5-month open-label randomized trial comparing olanzapine to risperidone found olanzapine increases insulin resistance and postprandial glucose/insulin responses (without clear fasting glucose or diabetes emergence differenc…
DOI: 10.4088/JCP.08m04446yel -
Metformin for Prevention of Weight Gain and Insulin Resistance with Olanzapine: A Double-Blind Placebo-Controlled Trial
This study investigates the efficacy of metformin in preventing weight gain and metabolic dysfunction in patients with schizophrenia treated with olanzapine, finding no significant differences in weight gain between metformin and placebo groups despite some metabolic improvement…
DOI: 10.1177/070674370605100310 -
Rapid Leptin Elevation after Initiation of Olanzapine?
This study investigates the rapid elevation of serum leptin levels following the initiation of olanzapine treatment in patients with schizophrenia and its potential implications for weight gain.
DOI: 10.1159/000099945 -
A Naturalistic Randomized Placebo-Controlled Trial of Extended-Release Metformin to Prevent Weight Gain Associated With Olanzapine in a US Community-Dwelling Population
This pilot study demonstrates that adjunctive metformin is effective and well tolerated in preventing weight gain associated with olanzapine in community-dwelling adults with various psychiatric disorders over a 24-week period.
DOI: 10.1097/jcp.0000000000000469 -
Deep brain stimulation in treatment resistant schizophrenia: PET changes post-stimulation
Nonclinical evaluation shows that samidorphan co-administered with olanzapine mitigates olanzapine-induced weight gain and adiposity in female rats and reduces weight gain and abdominal adiposity in female cynomolgus macaques, suggesting SAM can preserve olanzapine efficacy whil…
DOI: 10.1016/j.euroneuro.2018.11.599 -
Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: A multicentric, double-blind, placebo-controlled trial
This study investigates the efficacy of metformin as an adjunctive treatment to control body weight and metabolic dysfunction in patients with schizophrenia or bipolar disorder undergoing olanzapine therapy, finding that metformin led to a modest weight loss and stable insulin r…
DOI: 10.1016/j.schres.2007.03.029 -
A Comparison of the Effects of Olanzapine and Risperidone Versus Placebo on Ghrelin Plasma Levels
This study investigates the effects of olanzapine and risperidone on plasma ghrelin levels and weight gain in healthy subjects, finding that olanzapine significantly increases weight and decreases ghrelin AUC compared to placebo and risperidone.
DOI: 10.1097/jcp.0b013e3181613325 -
Increased Food Intake and Energy Expenditure Following Administration of Olanzapine to Healthy Men
Short-term olanzapine in healthy men increases food intake and resting energy expenditure, causing about 2.6 kg of weight gain over two weeks, driven by increased caloric intake rather than reduced activity or insulin resistance, with early metabolic changes including altered ad…
DOI: 10.1038/oby.2010.6