NADD Bulletin Volume IX Number 6 Article 2

Complete listing

Metabolic Effects of the Atypical Antipsychotic Agents: A Retrospective Review of Weight Changes in Individuals with Dual Diagnosis

Edwin J. Mikkelsen, M.D. 
The Mentor Network
Karen Shedlack, M.D.
McLean Hospital 
Ronda Williams, R.Ph.
Massachusetts Department of Mental Retardation

In recent years, it has become increasingly apparent that the atypical antipsychotic agents can contribute to weight gain and produce other deleterious metabolic effects (Haupt & Newcomer, 2001), which are often referred to as "metabolic syndrome."  (Ryan &Thakore, 2002).  The elements of metabolic syndrome include excessive weight and a predisposition to diabetes mellitus-type II, as well as cardiovascular and cerebrovascular morbidity.

While weight gain commonly precedes the onset of diabetes in those who take antipsychotic medications, it is not always seen. This common side effect has been well documented in the general psychiatric literature. The most current information comes from the large multi-center investigation referred to as the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) that was funded by the National Institute of Mental Health (Lieberman et al., 2005). The total cohort involved 1,493 patients who were randomly assigned to receive one of five medications for up to 18 months. The specific medications utilized were olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone. Weight gain was the most pronounced for those individuals in the olanzapine group, with an average weight gain of two lbs per month. The olanzapine group also had the highest rate of metabolic effects, such as increases in glucose, glycosylated hemoglobin, total cholesterol, and triglycerides. Weight gain was significantly less pronounced for the risperidone group.

There have only been a few studies that have addressed this issue in individuals with developmental disabilities. Risperidone has received the most attention with regard to weight gain in individuals with developmental disabilities. In a controlled study comparing risperidone and placebo for the treatment of aggressive behavior in children, adolescents, and adults with mental retardation and autism, the authors noted substantial weight gain in all age groups (Hellings, Zarcone, Crandall, Wallace, & Schroeder, 2001). Cohen et al. (2001) performed a retrospective review of 39 individuals with developmental disabilities who were treated with risperidone, and reported weight gain in 37 of the 39 individuals. They also noted that caloric restriction was not helpful in reducing the weight gain and that the restriction of calories did not produce any behavioral deterioration.


In order to further investigate this phenomenon, we reviewed the pre- and post-weight data for 19 adult individuals with developmental disabilities who were treated with olanzapine and 13 who had received risperidone. All of these individuals resided in a large, state-operated residential facility.

Olanzapine Cohort

In this group, there were seven females and 12 males; the duration of treatment ranged from 14 to 90 months, with an average of 53.3 months. Their ages ranged from 40 to 80 years, with an average age of 61 years. The range of cognitive impairment ranged from moderate to profound levels of mental retardation. The daily dosage ranged from 5mg to 27.5 mg, with an average daily dose of 11.8 mg. Thirteen of the individuals were receiving typical antipsychotics when the olanzapine was begun, and one individual was receiving risperidone. Seven of the participants were receiving lower doses of the typical antipsychotics at the time of this review, as the original agent had not yet been completely discontinued.

Risperidone Cohort

We performed a similar review of 13 individuals who had received risperidone for an average of 81 months (range 33 months to 129 months). The average age was 58.4 years, and there were 5 females and 8 males. The range of cognitive impairment for this group was also from moderate to profound levels of mental retardation. Ten of these individuals had received typical antipsychotic agents prior to being transitioned to risperidone, but none were receiving a second antipsychotic agent at the time of this review. The average dose of risperidone was 5.7 mg (range 0 to 12 mg).


Olanzapine Cohort

With regard to their weight status, seven individuals actually lost weight during the time they were receiving olanzapine (range 1 to 23 pounds; average weight loss 13.7 pounds). One individual's weight remained the same. Eleven individuals experienced weight gain that ranged from 5 to 31 pounds, with an average of 14.8 pounds. The average change in weight for the entire group was a gain of 3.8 lbs, over the entire length of time on olanzapine, which averaged 53.3 months. Expressed as a percent of average pre-olanzapine weight, the distribution was as follows:  two individuals experienced a weight gain of less than 5%; four between 5% and 10%; and five greater than 10%. The single greatest amount of weight gain was 31 pounds (from 115 to 146) over 60 months, which represents a 27% weight gain over the individual's pre-olanzapine weight. The percent of weight gain for the other four whose weight increased by greater than 10%, was considerably less than 20%.

Risperidone Cohort

The weight of two of the individuals in the risperidone cohort was unchanged at follow-up. Five individuals actually lost weight. The range of weight loss was from 4 to 39 lbs, with an average weight loss of 23.2 lbs. All of the individuals who lost weight had been receiving a typical antipsychotic agents before they were transitioned to risperidone. Six individuals gained an average of 10.2 lbs (range 5 to 20 lbs).  The average change in weight for the entire risperidone group was a loss of 3.5 lbs. Expressed as a percent of average pre-risperidone weight, the distribution was as follows:  4%, 5% (2), 7%, 8%, and 14%. Two of the individuals who gained weight had not been receiving an antipsychotic agent at the time they were started on risperidone, but the remaining four were transitioned from typical antipsychotic agents.


These findings are consistent with the CATIE study in that the olanzapine-treated group gained more weight than the risperidone group. However, the degree of weight gain for our olanzapine group was considerably less than the average of two pounds per month reported in the CATIE study. There are a few published reports concerning the use of olanzapine in individuals with developmental disabilities, but they do not report on the issue of weight. The findings of this retrospective review clearly differ from the two published reports regarding risperidone use. These findings are consistent with the CATIE study, in that the olanzapine group produced more weight gain than the risperidone group.

We believe these findings are of interest, as they suggest that weight gain with the atypical antipsychotic agents olanzapine and risperidone is not as inevitable as much of the existing literature would suggest. These individuals had significant cognitive disabilities, but there is no reason to believe that their developmental disability would significantly affect their metabolic status; and, as noted above, prior studies with risperidone have reported substantial weight gain in individuals with developmental disabilities. It is possible that the weight loss in the risperidone group was related to the discontinuation of prior treatment with typical antipsychotic agents, as all of the five individuals who lost weight were also discontinued from a typical antipsychotic agent. The discontinuation of typical antipsychotic agents can produce considerable amounts of weight loss (Mikkelsen, Albert, & Upadhyaya, 1988). However, four individuals who were discontinued from typical antipsychotic agents gained weight on risperidone.

Our explanation for the lack of significant weight gain in this group of individuals relates to environmental factors, as weights are closely monitored in the facility in which they reside. Dietary interventions are implemented as soon as a gain in weight is detected, rather than after a substantial amount has occurred.

Related to the caloric control in our cohort, it is also important to note that these individuals did not have access to vending machines or other sources of junk food, due to their level of cognitive impairment and the structure of the facility.

An additional component to the weight-control effort was physical activity. Each individual in these groups had a specialized exercise program tailored to their cognitive and physical abilities. Specially trained physical activity therapists carried out the program. Thus, it seems likely that the lack of significant weight gain in these cohorts resulted from the combination of caloric control and a specialized exercise program.


This manuscript describes the results of a retrospective review of weight change in individuals with developmental disabilities who received olanzapine (N=19; average duration 53.3 months), and risperidone (N= 13; average duration 81.6 months) on a long-term basis. The average change in weight status for the olanzapine group was a gain of 3.8 lbs. The results for the risperidone cohort actually indicated that the average change for the entire group was a loss of 3.5 lbs. Thus, for these individuals, weight gain did not appear to be as significant a problem as often reported for the general population who receive olanzapine, and for individuals with developmental disabilities who receive risperidone. We believe the explanation for this lack of weight gain derives from dietary interventions and an active individualized exercise program that is designed to take into account each person's cognitive and physical disabilities.


Cohen, S., Glazewski, R., Khan, S., & Khan, A. (2001). Weight gain with risperidone among patients with mental retardation:  Effect of calorie restriction. Journal of Clinical Psychiatry, 62, 114-116.

Haupt, D. W. & Newcomer, J. W. (2001). Hyperglycemia and antipsychotic medications. Journal of Clinical Psychiatry, 62, 15-26.

Hellings, J. A., Zarcone, J. R., Crandall, K., Wallace, D., & Schroeder, S. R. (2001). Weight gain in a controlled study of risperidone in children, adolescents, and adults with mental retardation and autism. Journal of Child & Adolescent Psychopharmacology, 11, 229-238.

Lieberman, J. A., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., et al. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. The New England Journal of Medicine, 353, 1209-1223.

Mikkelsen, E. J., Albert, L. G., & Upadhyaya, A. (1988). Neuroleptic-withdrawal cachexia (Letter to the editor). New England Journal of Medicine, 318, 929.

Ryan, M. C. & Thakore, J. H. (2002). Physical consequences of schizophrenia and its treatment:  The metabolic syndrome. Life Sciences, 71, 239-257.