First-Time Antipsychotic Use Linked to Rapid Weight Gain, Adverse Metabolic Changes in Kids

November 4, 2009 — First-time, second-generation antipsychotic use in children and adolescents is associated with rapid and significant weight gain as well as varied adverse metabolic changes, new research shows.

A unique study of 272 antipsychotic-naive pediatric patients showed that after a median of 10.8 weeks of treatment with antipsychotic medications, study subjects gained an average of 18.7 pounds with olanzapine, 13.4 pounds with quetiapine, 11.7 pounds with risperidone, and 9.7 pounds with aripiprazole. A total of 10% to 36% of study participants transitioned to overweight or obese status within 11 weeks.

In comparison, a "control" group of 15 patients who refused treatment with antipsychotic medications or were nonadherent experienced an average weight gain of 0.4 pounds during the same time period.

Furthermore, the study also showed that adverse changes reached statistical significance for olanzapine only for fasting glucose, insulin, and insulin resistance. Moreover, quetiapine showed significant worsening of total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and ratio of triglycerides to HDL cholesterol.

With risperidone, only triglycerides increased significantly. However, at least during the first 3 months of treatment, baseline-to-endpoint changes were not significant with aripiprazole or in the untreated comparison group, the authors report.

"This study adds to the prevailing suspicion that antipsychotic use in children and adolescents significantly increases the risk for early, age-inappropriate weight gain as well as metabolic abnormalities," principal investigator Christoph U. Correll, MD, Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, Glen Oaks, and the Feinstein Institute for Medical Research, Manhasset, New York, told Medscape Psychiatry.

"Secondly, these abnormalities do not appear to be as much related to a new onset of illness or hospitalization but really seem to be due to the medications themselves," Dr. Correll added.

The study was published in the October 28 issue of the Journal of the American Medical Association.

Safer Alternative to First-Generation Drugs?

Use of atypical antipsychotics in children and adolescents with psychotic disorders, bipolar disorder, and nonpsychotic mental disorders has flourished largely because of the lack of acute adverse effects such as akathisia and tardive dyskinesia, which are typically associated with first-generation agents.

"Second-generation antipsychotics were embraced when they were introduced because these acute, parkinsonian-like, in-your-face side effects were much less, and it was felt that the absence of these effects with the newer agents would help overcome issues such as patient dysphoria and noncompliance associated with first-generation medications," said Dr. Correll.

However, following published data in adults that linked atypical antipsychotics to more chronic effects including weight gain and metabolic abnormalities in adults, the researchers launched the current study.

"At that time there was very little known about the effect of atypicals in children and adolescents, and since I work in early intervention and prevention of psychosis in adolescents and young adults, we felt this warranted investigation to determine both clinical treatment and biological predictors of adverse events," said Dr. Correll.

Unique Opportunity

The Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SAIETY) study was conducted between December 2001 and September 2007 at tertiary-care, academic inpatient and outpatient clinics in Queens, New York.

Participants included 272 antipsychotic-naive patients aged 4 to 19 years. A total of 130 participants (47.8%) had mood spectrum disorder, 82 patients (30.1%) had schizophrenia, and 60 participants (22.1%) had disruptive or aggressive behavior spectrum disorders.

The primary outcome measures included changes in weight gain and changes in lipid or metabolic parameters after 12 weeks of treatment with 1 of the 4 most commonly used antipsychotics including olanzapine, quetiapine, aripiprazole, or risperidone.

"This study provided us with a unique opportunity to follow these children and adolescents and their families at a time of great distress, but also to evaluate their very first encounter with these medications and assess the effects unconfounded by prior treatment. In contrast, in adults, you may be assessing the tip of the iceberg, where you are only able to look at the last 3 months of a 20-year illness and treatment course," said Dr. Correll.

Weight Gain Not the Only Possible Mechanism

The rapid and significant weight gain during a relatively short treatment period came as a surprise said Dr. Correll. The second surprising finding was that even though the weight gain was pervasive across all 4 medications, the metabolic signature of the agents was different.

"We always thought that most of the effect on glucose and lipid metabolism was really coming through the indirect effect of weight gain," Dr. Correll said. "So in other words, if you gain weight, with or without the medications, it affects both glucose and lipid metabolism. This appears to be true to some degree, but there also appears to be a weight-independent effect that some of these medications have more than others."

For instance, Dr. Correll said, olanzapine appeared to adversely affect both glucose and lipid metabolism, whereas quetiapine and risperidone had a much more benign affect on these parameters. Surprisingly, he said, even though aripiprazole was associated with significant weight gain, it was not associated with any significant lipid or glucose abnormalities and was similar to the control group.

The researchers found age had no effect on risk for weight gain or metabolic abnormalities. When they looked at dose effect, they found that olanzapine had no dose effect on weight gain but that dose did affect metabolic parameters.

However, higher doses of risperidone predicted both an increase in weight and an increase in triglycerides, a finding that suggests this drug may promote weight gain, which in turn affects metabolic parameters.

More Frequent Monitoring

These findings, said Dr. Correll, indicate a need for frequent cardiometabolic monitoring in this patient population. Finally, he said, in view of poor physical health outcomes and suboptimal metabolic monitoring in the severely mentally ill, the benefit of second-generation antipsychotic medications must be balanced against their cardiometabolic risks through careful assessment of the indications for their use, consideration of lower-risk alternatives — including nonpharmacological approaches, and proactive adverse effect monitoring and management.

"These medications are not benign and can have side effects that can have potential long-term complications that are associated with endocrine and cardiovascular illness, so making the decision to use this medication group is a serious step, and it should be treated as such. We really need to carefully weigh the risks and benefits — the risk of the illness and the risk of the medication," said Dr. Correll.

Widespread Use Should be Reconsidered

In an accompanying editorial, Christopher K. Varley, MD, and Jon McClellan, MD, from Seattle Children's Hospital, Washington, also call for greater caution when prescribing these medications. They describe the data reported by Dr. Correll and his team as "timely and sobering."

They point out that studies support the use of second-generation antipsychotics for autism, schizophrenia, bipolar disorder, aggression, and tics. However, they note, most of the trials of these medications are short-term and have methodological limitations.

Although these medications can be lifesaving for youth with serious psychiatric illnesses, write Dr. Varley and Dr. McClennan, given the risk for weight gain and long-term risk for cardiovascular and metabolic consequences, their widespread use in this patient population should be reconsidered.

The authors also note that although there are guidelines governing the use of these medications, it is not clear whether clinicians adhere to them or whether adherence improves outcomes.

Finally, they note that much of the research into atypical antipsychotic agents is supported by industry-sponsored studies. In light of this, they call for large-scale independently funded investigations that will establish the long-term safety and benefit of these agents in children and adolescents.

"Until those data are available, consideration of less risky treatment interventions and scrupulous attention to metabolic parameters in children and adolescents who receive atypical antipsychotic medications are essential," they write.

Dr Correll has disclosed being a consultant or receiving honoraria from AstraZeneca, Bristol Myers Squibb, Cephalon, Eli Lilly, Intra-Cellular Therapeutics, Medicure, OrthotMcNeill-Lanssen, Otsuka, Organon, Pfizer, Schering-Plough, Solvay, Supernus, Vanda, and Wyeth. He has also disclosed that he has served on the speaker’s bureau of AstraZeneca, Bristo-Myers Squibb/Otsuka, and Pfizer. For information on the financial disclosures of the other investigators, see the full study.

JAMA. 2009;302:1765–1773. Abstract

Clinical Context

 

Study Highlights

 

• Included were children and adolescents aged 4 to 19 years who had 1 week or less of lifetime exposure to antipsychotic medication and psychiatric illness needing antipsychotic treatment.
• Excluded were those receiving more than 1 antipsychotic medication, with active eating disorder, acute medical conditions, thyroid disease, or pregnancy or lactation.
• Psychiatric diagnoses were determined by chart review and clinical interview, and Tanner pubertal stage was determined by examination.
• Primary outcomes were absolute and relative weight change.
• Secondary outcomes included fat mass, waist circumference, lipid profile, insulin resistance measured by the homeostasis model of insulin resistance and metabolic syndrome criteria.
• Individuals were assessed after 8 or more hours of fasting at baseline and at 4, 8, and 12 weeks.
• Of 505 youth who were eligible, 338 were enrolled (66.9%) and 205 completed the study (61.7%).
• 48% had mood spectrum disorder, 30% had schizophrenia spectrum disorder, and 22% had disruptive or aggressive spectrum disorder.
• Participants received 12 weeks of treatment with one of 4 atypical agents: olanzapine, risperidone, quetiapine, or aripiprazole.
• The comparison group consisted of 15 patients who refused or ended antipsychotic treatment.
• After a median of 10.8 weeks, weight increased by 8.5 kg in the olanzapine group, 6.1 kg in the quetiapine group, 5.3 kg in the risperidone group, and 4.4 kg in the aripiprazole group.
• The untreated comparison group had nonsignificant weight gain (0.2 kg).
• Each medication was also associated with a significant increase in waist circumference and fat mass and shifts to overweight and obese status.
• When 14% and 21% greater than unadjusted weight gain was used as a threshold, similar rankings of weight increase was seen for the 4 atypical agents.
• At 11 weeks, 10% to 36% of patients transitioned from normal to overweight or obese status.
• Metabolic changes were not significant in the untreated comparison group and the aripiprazole group.
• Triglyceride levels were not increased in the untreated comparison group and the aripiprazole group.
• Those receiving risperidone had increased triglyceride levels (9.7 mg/dL).
• For olanzapine and quetiapine, levels of total cholesterol increased significantly (15.6 and 9.1 mg/dL, respectively), as well as triglyceride levels (24.3 and 37.0 mg/dL, respectively), non-HDL cholesterol levels (16.8 and 9.3 mg/dL, respectively), and the ratio of triglycerides to HDL cholesterol.
• Patients receiving olanzapine had the highest incidence rates of metabolic syndrome, followed by patients receiving quetiapine.
• Quetiapine and risperidone increased triglyceride levels but not glucose abnormalities.
• Pubertal status was unchanged by the 4 agents.
• The incidence of metabolic changes was increased with dose for risperidone and olanzapine but not for the other 2 agents.
• The authors concluded that all 4 agents increased body weight and body mass index but that their effect on metabolic outcomes was different.

Clinical Implications

 

• The atypical antipsychotic agents olanzapine, quetiapine, risperidone, and aripiprazole are associated with significant weight gain and an increase in body mass index, waist circumference, and fat mass in youth at 11 weeks of treatment.
• Metabolic changes associated with 11 weeks of treatment with atypical antipsychotics vary by the agent used.