Common, Predictable, Potentially Serious
Antipsychotics may act on the hypothalamic feeding center and stimulate the appetite directly. Antagonism of serotonin (5-HT2C) or histamine (H1) and other receptors and neurotransmitters may play a role in antipsychotic-related weight gain.
Agents that stimulate the 5-HT2C receptors such as fenfluramine and M-chlorophenyl-piperazine have been associated with weight loss; agents that antagonize these receptors are thought to increase appetite and to cause weight gain. Agents that antagonize the histamine receptor induce weight gain, and there is an exponential relationship between the antipsychotics’ H1 affinity and the potential for inducing weight gain. Clozapine and olanzapine have strong affinity for 5-HT2C and H1 receptors; these atypicals are the greatest promoters of weight gain among antipsychotics. Clinical trials have shown convincingly that atypical antipsychotics pose a greater risk of weight gain and central adiposity than do most of the older typical antipsychotics.
Peripheral antagonism of H1 receptors appears to interfere with satiety signals; affinity to histamine H1 receptors is strongly correlated with weight gain potential. Weight gain is associated with increased morbidity and mortality in a wide range of conditions, including hypertension, coronary heart disease, cerebrovascular disease, type 2 diabetes mellitus, various cancers, sleep apnea, and respiratory problems. Weight gain causes negative psychosocial stress and may compromise compliance.
The higher the BMI, the greater the risk of sudden death, cerebrovascular accident, and congestive heart failure in both sexes. The ratio of waist girth to hip girth is significantly associated with diabetes, hypertension, and gallbladder disease in women 40 to 59 and with menstrual abnormalities in women 30 to 39 years old, even in women with comparable total body fat.
Obese individuals with high waist-hip ratios show decreased hepatic extraction of insulin, higher posthepatic insulin levels, and more insulin resistance. Clozapine and olanzapine are associated with the greatest weight gain, followed by risperidone, ziprasidone (and aripiprazole); reports on quetiapine have been inconsistent. Weight gain associated with quetiapine, risperidone, and ziprasidone tends to plateau within the first few months, whereas patients on clozapine or olanzapine may tend to continue gaining weight for 9 months or more. In the CATIE report, cited above, patients on quetiapine gained more weight than patients on risperidone.
There is considerable evidence, particularly in patients with schizophrenia, that treatment with second generation antipsychotics can cause a rapid increase in body weight in the first few months of therapy and that it may not reach a plateau even after one year of treatment. Adolescents and young adults are particularly susceptible to antipsychotic induced weight gain. Adolescents are particularly susceptible to metabolic dysregulation; extreme weight gain (> 7% baseline body mass) for olanzapine and risperidone was observed in adolescent inpatients, and extreme weight gain was seen in 78% of patients of an adolescent group (for 6 months the weight gain averaged 1.2 kg/month without leveling off). Risperidone’s apparent metabolic advantage for adults does not seem to be present for children and adolescents. Risperidone’s effect on prolactin may explain this metabolic disturbance. Children and adolescents have an exquisite end-organ sensitivity related to prolactin levels.
The extent of weight gain reported is indeed worrisome, if not alarming. During 12 weeks of follow-up, 19 of the 21 (90.5%) patients treated with olanzapine, and 9 of the 21 (42.9%) patients treated with risperidone showed a 7% increase of weight, which is considered extreme weight gain. The relative average increase of weight was 11.1% in the olanzapine group and 6.6% in the risperidone group. The average absolute weight gain for olanzapine and risperidone was 7.2 kg and 3.9 kg, respectively. The rates were 1.5 (olanzapine) and 1.9 (risperidone) times higher than the rates reported in adults. Olanzapine may have caused more robust weight gain because of its combined 5-HT2C and histamine-1 antagonistic effects. Risperidone exerts mostly 5-HT2C inhibitory and a weak H1 antagonistic effect. Male gender was a prominent risk factor, with significantly more males (67.7%) than females (42.1%) showing extreme weight gain. Concerns about weight gain were particularly higher for those subjects with lower baseline weight; they gained more weight during treatment with atypical antipsychotics than did patients with a higher BMI. Neither efficacy of the neuroleptic treatment (change in PANSS) nor its dosages was associated with the proportional weight gain. The CATIE study, in adults, confirmed that olanzapine poses serious heath risks; olanzapine was the most weight promoting and, in this regard, the most toxic of the second generation antipsychotics studied, and was associated with a greater increase in glycosylated hemoglobin, total cholesterol, and triglycerides.
The ranking of atypicals regarding weight gain induction in children and adolescents is: clozapine > olanzapine > risperidone > quetiapine > aripiprazole > ziprasidone. Loss of weight is very difficult, even in highly motivated persons. Obesity is related to multiple health risks and to a higher prevalence of psychiatric disorders in children and adolescents. The American Academy of Pediatrics has advised the membership to take a more active role in stemming the increasing prevalence of obesity in childhood and adolescence. Child psychiatrists can contribute to identification and management of this complex and vexing problem. Obesity is a major source of multiple heath risks, and a major factor in self-esteem difficulties. Obesity is clearly associated with an increased incidence of depression and anxiety disorders, school and vocational difficulties. Obese children have a higher risk of suicide. The importance of taking detailed family and medical histories and of identifying risk factors for obesity and diabetes mellitus should not be underemphasized (detecting acanthosis nigricans, as a marker for diabetes mellitus, etc). Barnhill proposes an aggressive treatment of obesity.