Antipsychotic medications manage psychiatric conditions like schizophrenia and bipolar disorder. While effective, a significant side effect of these medications is weight gain. This weight gain can lead to further health complications, including an increased risk of type 2 diabetes and cardiovascular disease. Antipsychotic-induced weight gain is complex, involving several biological and behavioral mechanisms.
Influence on Appetite and Satiety
Antipsychotics, especially second-generation (atypical) types, influence appetite and satiety by interacting with neurotransmitter receptors in the brain. These interactions lead to increased hunger and reduced feelings of fullness, resulting in greater caloric intake. The most prominent mechanisms involve blocking histamine H1 and serotonin 5-HT2C receptors.
Blocking histamine H1 receptors in the hypothalamus, a brain region that regulates food intake, increases appetite and food consumption. This blockade activates AMP-activated protein kinase (AMPK), promoting feeding, and reduces histamine release, which normally represses food intake. Medications like clozapine and olanzapine, known for causing significant weight gain, have a high affinity for H1 receptors.
Similarly, blocking serotonin 5-HT2C receptors can disinhibit appetite and diminish feelings of satiety. Serotonin regulates mood, sleep, and appetite; interference with its 5-HT2C receptor disrupts signals for fullness. This leads to increased food cravings and consumption, further contributing to weight gain. Some antipsychotics also interact with muscarinic M3 and alpha-adrenergic receptors, which also affect appetite regulation.
Alterations in Metabolism
Beyond appetite effects, antipsychotics directly impact the body’s metabolic processes, independent of changes in food intake. These medications disrupt how the body processes glucose and fats, favoring fat storage and increasing metabolic complication risk.
A metabolic alteration is the development or worsening of insulin resistance. Insulin is a hormone that helps cells absorb glucose from the bloodstream for energy. When insulin resistance occurs, cells become less responsive to insulin, leading to higher blood sugar levels and increased insulin production by the pancreas. Excess insulin can promote fat storage, particularly in the abdominal area, contributing to weight gain and an elevated risk of type 2 diabetes. Some research suggests antipsychotics may directly inhibit insulin signaling in cells and even damage pancreatic cells that produce insulin.
Antipsychotics also disrupt lipid metabolism, leading to changes in blood fat levels. This commonly includes increases in triglycerides and low-density lipoprotein (LDL) cholesterol, while sometimes decreasing high-density lipoprotein (HDL) cholesterol. These lipid disturbances can occur independently of weight gain and contribute to fat accumulation and an increased risk of cardiovascular disease. These metabolic shifts mean the body becomes less efficient at burning fat for energy and more prone to storing it.
Reduced Physical Activity
A common side effect of antipsychotic medications is sedation or lethargy, which can reduce physical activity levels. Some antipsychotics, such as chlorpromazine and olanzapine, are known for causing sleepiness and a lack of motivation. This decreased energy makes it challenging to engage in regular movement or exercise, even simple daily activities.
When physical activity decreases, the body expends fewer calories, leading to lower overall energy expenditure. If caloric intake remains the same or increases due to appetite changes, this creates a positive energy balance where more calories are consumed than burned. Over time, this imbalance contributes directly to weight gain, independent of the medication’s direct physiological effects on metabolism or appetite. The reduction in physical activity, combined with other mechanisms, creates a challenge for individuals taking these medications.
Individual Differences and Genetic Predisposition
Not everyone experiences the same degree of weight gain when taking antipsychotics; considerable variability exists among individuals. This difference attributes to a combination of factors, including individual genetic variations. Genetic makeup influences how a person metabolizes these drugs, affecting drug concentrations, or how their body responds to the drug’s effects on appetite and metabolism.
Genes involved in regulating food intake, like the melanocortin 4 receptor (MC4R), have been linked to susceptibility to antipsychotic-induced weight gain. Variations in genes related to histamine and serotonin receptors also play a role in how a person’s appetite and metabolic responses are affected.
Beyond genetics, factors like pre-existing metabolic conditions, baseline weight before medication, and lifestyle habits also contribute to the extent of weight gain experienced. These individual differences highlight the importance of personalized approaches to managing antipsychotic treatment side effects.