Management of obesity induced by psychotropic and neurological drugs: mechanisms of weight gain, risk levels, and clinical strategies

Many medications can cause weight gain, including certain psychoactive drugs (especially olanzapine and risperidone), tricyclic antidepressants, antiepileptic drugs, insulin, and sulfonylureas. Other medications associated with weight gain include cyproheptadine (an antihistamine), beta-blockers, and glucocorticoids. I. The Relationship Between Psychotropic or Neurological Medications and Weight Gain 1. The Relationship Between Antipsychotics and Weight Gain: Different antipsychotics have varying effects on weight and metabolism. Weight gain, metabolic syndrome (including diabetes and dyslipidemia), diabetic ketoacidosis, and cardiovascular disease are often associated with second-generation antipsychotics (SGAs) and also with the use of first-generation antipsychotics (FGAs, also known as nerve blockers, traditional or typical antipsychotics). While no SGA is completely unaffected by metabolism, the effects of different drugs on metabolism vary considerably. Studies have shown that clozapine and olanzapine cause the greatest weight gain, at 4.4 kg and 4.2 kg respectively, followed by risperidone at 2.10 kg. The Clinical Trial of Antipsychotic Drugs (CATIE) study on the effectiveness of interventions found that adult patients using olanzapine gained an average of about 1 kg per month over 18 months; 30% of these patients gained 7% or more of their initial weight. Aripiprazole, lurasidone, pipemaserin, and ziprasidone had the lowest associated risk of weight gain. 2. Relationship between antidepressants and weight gain: The long-term weight gain potential of antidepressants varies greatly. Tricyclic antidepressants can cause significant weight gain, especially amitriptyline, clomipramine, doxepin, and imipramine. Amitriptyline caused the most significant weight gain among tricyclic antidepressants (1.8 kg). Other specific tricyclic compounds associated with weight gain include nortriptyline. The effect of selective serotonin reuptake inhibitors (SSRIs) on weight is not very clear. Short-term use of fluoxetine and sertraline can lead to weight loss; conversely, long-term use of certain SSRIs may cause weight gain, with paroxetine considered an SSRI associated with maximum weight gain. Long-term use of mirtazapine (a norepinephrine and specific serotonergic antidepressant) is also associated with weight gain (1.5 kg). 3. Relationship between neurological and mood stabilizers and weight gain: Valproate (valproic acid) and carbamazepine, antiepileptic drugs commonly used to treat bipolar disorder, can cause weight gain. Some studies have found that 15% to 70% of patients taking valproate for epilepsy experience a weight gain greater than 4 kg. Carbamazepine is associated with a weight gain of 1 kg. Another study showed that after 1.5 months of using gabapentin, a weight gain of approximately 2.2 kg was observed. Lithium, a mood stabilizer used to treat bipolar disorder, can also cause weight gain. II. Mechanisms of weight gain caused by psychotropic or neurological drugs: The pharmacological mechanisms by which antipsychotic drugs cause weight gain may be closely related to receptor activity. The most likely reason for the weight gain effects of olanzapine and clozapine is their antagonistic or reverse agonistic effect on serotonin 2C receptors and their antagonistic effect on histamine H1 receptors. Both of these receptors are involved in the hypothalamus's control of food intake. Other clearly related receptors include alpha-adrenergic receptors, serotonin receptors, and dopamine D2 receptors (DRD2) involved in hypothalamic appetite control and response. The effects of antipsychotic drugs on weight vary considerably, and individual responses also differ greatly. While lifestyle and diet may contribute, genetic factors are clearly also involved. Polymorphisms in many common candidate genes related to weight control and energy and lipid metabolism have been found to be associated with weight gain after antipsychotic drug treatment, with the strongest associations being promoter polymorphisms in the 5-HT2C receptor and leptin gene. Antidepressants such as amitriptyline, clomipramine, doxepin, and imipramine exert their sedative, weight-gain, and anticholinergic side effects by blocking the reuptake of serotonin and norepinephrine, and also exhibiting high affinity for histamine H1 and muscarinic M1 receptors. Valproic acid may induce obesity for the following reasons: increased appetite, hyperleptinemia and leptin resistance, insulin resistance, and increased fat storage due to inhibition of fatty acid metabolism by β₂ oxidation, which inhibits fatty acid metabolism. III. Interventions for Weight Gain Caused by Psychotropic or Neurological Drugs Clinically, treatment strategies for weight gain and other metabolic problems can be selected based on various factors, including the patient's response to different antipsychotic drugs, the severity of metabolic disorders, and the patient's willingness to make lifestyle changes. 1. Lifestyle Intervention: Lifestyle intervention should be one of the first-line strategies and, in most cases, should continue after other interventions are added. On average, lifestyle intervention can reduce weight by more than 3 kg and decrease BMI by more than 1 kg/m² compared to the control group. Lifestyle intervention can improve weight gain associated with the first use of antipsychotic drugs. 2. Enhanced Monitoring: It is recommended to use psychotropic or neurological drugs with neutral effects on weight in clinical practice, and to fully inform patients when using these drugs, while pre-assessing the potential weight-related effects of each drug. More frequent assessments of weight, blood lipids, and blood glucose should be performed on individual patients (such as those with significant weight gain). 3. Replace or use psychotropic or neurological medications with lower effects on weight gain: Studies have shown that replacing medications with a relatively high risk of weight gain or dyslipidemia (such as olanzapine, quetiapine, and risperidone) with lower-risk medications (aripiperazole or ziprasidone) can often (but not always) effectively promote weight loss and improve lipid profiles. Data indicate that the following medications have the lowest tendency to cause weight gain: haloperidol, ziprasidone, lurasidone, aripiprazole, amisulpride, and asenapine. Fluoxetine is a selective serotonin reuptake inhibitor, clinically used to treat adult depression, obsessive-compulsive disorder, and bulimia nervosa. Studies on the weight loss effect of fluoxetine in obese patients with depression showed that patients using fluoxetine for 29 weeks experienced a weight loss of (12.3 ± 3.0) kg. Zonisamide is a novel antiepileptic drug that may lead to weight loss by lowering serum leptin levels. Topiramate is a highly effective broad-spectrum antiepileptic drug that can significantly reduce weight and blood pressure in obese patients, primarily through reducing calorie intake and hormonal imbalances. 4. Combination with aripiprazole: Aripiprazole adjunctive therapy can be used as an intervention strategy for weight gain associated with clozapine and olanzapine. The pharmacological mechanism may be related to partial agonism of certain serotonin receptors. 5. Combination with metformin: For high-risk individuals with diabetes, metformin can be used as adjunctive therapy to reduce weight gain associated with antipsychotic medications. Trials have shown that metformin can reduce weight by approximately 3 kg compared to placebo; and for patients receiving antipsychotic medication for the first time, metformin can reduce weight gain by approximately 5 kg.