Given the efficacy and safety profiles of atypical antipsychotics, their potential to cause weight gain represents not a barrier to access but a side effect to be managed. Behavioral and/or drug interventions can help protect patients from the medical risks and social consequences of weight gain during antipsychotic treatment.
Let’s look at possible mechanisms of antipsychotic-induced weight gain and a rational strategy for controlling weight in patients taking these medications. This strategy applies to all atypical antipsychotics and psychiatric diagnoses.
Mechanisms of weight gain
Neuroleptic antipsychotics may act on the hypothalamic feeding center and directly stimulate appetite, a dynamic that was suggested 20 years ago.1 More recent evidence suggests that antagonism of serotonin (5-HT2C) or histamine (H1) receptors may play a role in antipsychotic-related weight gain. Other neurotransmitters and receptors may also be involved.
Serotonin receptor antagonism. Agents that stimulate 5-HT2C receptors—such as fenfluramine and M-chlorophenylpiperazine2 —have been associated with weight loss. Conversely, agents that antagonize these receptors have been hypothesized to increase appetite and cause weight gain.3
For example, a strain of mice craved carbohydrates and became obese after the genes for 5-HT2C receptors were removed.4 Atypical antipsychotics also antagonize 5-HT2C receptors more than the older neuroleptics do, which may explain the atypicals’ greater associated risk for weight gain.
Histamine receptor antagonism. Other researchers have suggested that antipsychotic-induced weight gain is associated less with serotonin receptors than with histamine receptor antagonism:
- Astemizole—a potent H1 receptor antagonist used to treat allergic rhinitis—was the first medication associated with weight gain by this mechanism.5
- Wirshing et al6 recently reported an exponential relationship between antipsychotics’ H1 receptor affinities and maximum weight gain.
Clozapine and olanzapine have very strong binding affinity to both 5-HT2C and H1 receptors. This characteristic may explain why patients often experience increased appetite and weight gain while taking these antipsychotics.
Other neurotransmitters. Atypical antipsychotics have diverse pharmacologic profiles, and their interactions with dopamine and other neurotransmitter receptors produce a variety of effects (Table 1). These neurotransmitter systems and receptor subtypes appear to help regulate food intake and energy homeostasis and may play a role in weight gain associated with antipsychotic use.7 For example:
- Clozapine and olanzapine have a higher affinity for serotonin receptor subtypes 5-HT2A and 5-HT2C and for H1 and muscarinic (M1) receptors than they do for D2 receptors. This preferential antagonism of 5-HT2A versus D2 receptors is a defining characteristic of novel antipsychotics and explains why they offer broader efficacy and fewer side effects than the older neuroleptics. However, 5-HT2C receptor antagonism has been implicated as a cause of increased appetite.4
- Clozapine, but not olanzapine, also has a higher affinity for adrenergic (1) receptors than for D2 receptors. Clozapine is associated with greater mean weight gain than olanzapine, risperidone, or ziprasidone.8
- Risperidone—with a lower weight gain potential than most atypicals—displays high affinity for 5-HT2A and 1 receptors and a lower affinity for 5-HT2C receptors than for D2 receptors.8
- Ziprasidone’s weight gain potential is even less than risperidone’s, and the exact mechanism is unknown.8 Some animal studies suggest that ziprasidone’s effects on the noradrenergic system may explain its low weight gain potential.9
- Aripiprazole’s long-term weight gain potential is not yet known.
Table 1
RECEPTOR BINDING AFFINITIES OF ATYPICAL ANTIPSYCHOTICS
| Drug | Dopamine | Serotonin | ∂1 adrenergic | Histamine | Muscarinic | |
|---|---|---|---|---|---|---|
| D2 | 5HT2A | 5HT2C | H1 | M1 | ||
| Clozapine | + | ++++ | +++ | +++ | ++ | |
| Olanzapine | ++ | ++++ | ++++ | − | ++ | − |
| Quetiapine | + | + | + | +++ | ++ | − |
| Risperidone | ++++ | +++++ | ++ | + | +++ | − |
| Ziprasidone | ++++ | +++++ | + | 0 | ++ | − |
A strategy for managing weight gain
Four predictors of weight gain have been identified in patients with schizophrenia:
- better clinical outcome
- low baseline body mass index
- younger age
- increase in appetite during treatment.10
When appetite increases, patients are at risk of overeating to satisfy their hunger. An average increase of 500 calories per day will cause an average weight gain of 1 lb per week. Therefore, minimizing an increase in caloric intake may minimize weight gain.
One can lose weight by reducing caloric intake or increasing caloric output, such as with exercise. Thus, behavioral interventions focusing on both nutritional education and exercise are showing benefit in minimizing antipsychotic-related weight gain. The “wellness clinic” described by Wirshing et al achieved weight loss in patients taking antipsychotics through rigorous interventions, including education, exercise classes, and group support.6
A rational approach for minimizing weight gain in patients taking antipsychotics is summarized in Table 2. This strategy combines nutritional and exercise education and drug therapy, when indicated.
Effect of behavioral interventions
Many patients who have followed behavioral interventions that emphasize nutrition and exercise have lost at least some of the weight they gained during antipsychotic treatment:
- In a study by O’Keefe, nearly 80% of patients who gained >20 lbs while taking antipsychotics then lost at least 10 lbs while in behavioral intervention programs.11
- Patients with schizophrenia or schizoaffective disorder who experienced olanzapine-related weight gain lost weight while attending a 10-week Weight Watchers program.12
- Patients who gained weight while taking antipsychotics lost weight with a step-wise behavioral approach that included increasingly intensive interventions (self-weighing, food diaries, nutrition consultation, and attendance at a “wellness clinic”).6
- 70% of 74 psychiatric inpatients lost weight across 6 to 34 months with a reduced-calorie diet, group therapy, and behavior modification.13