Weight gain and fatigue are among the most distressing adverse effects associated with psychiatric medications. These side effects not only compromise treatment adherence but also contribute significantly to cardiometabolic comorbidities, increasing morbidity and mortality in patients with serious mental illnesses. The mechanisms, however, are complex, multifactorial, and vary between drug classes.

🔬 Mechanisms Behind Weight Gain and Fatigue with Psychiatric Medications

1️⃣ Hypothalamic Dysregulation of Appetite and Satiety

• Histamine H1 receptor antagonism (e.g., olanzapine, clozapine) reduces satiety, promotes hyperphagia.

• 5-HT2C receptor antagonism (e.g., olanzapine, mirtazapine) disrupts hypothalamic regulation of appetite.

• Increased leptin resistance leads to impaired satiety signaling.

Net Effect: Increased appetite, craving for calorie-dense foods, hyperphagia.

2️⃣ Insulin Resistance and Glucose Dysregulation

• Atypical antipsychotics can induce peripheral insulin resistance independent of weight gain.

• Decreased insulin sensitivity leads to hyperinsulinemia, further stimulating lipogenesis and fat storage.

• Impaired glucose metabolism → fatigue, reactive hypoglycemia, increased appetite.

3️⃣ Disruption of Circadian Rhythms and Sleep-Wake Regulation

• Sedating agents (antipsychotics, mirtazapine, TCAs, benzodiazepines) reduce daytime activity and alter sleep architecture.

• Disrupted circadian rhythms influence metabolic pathways (glucose tolerance, cortisol, ghrelin-leptin balance).

• Poor sleep → increased appetite for carbohydrates and fats.

4️⃣ Mitochondrial Dysfunction and Fatigue

• Psychotropics, especially mood stabilizers like valproate and lithium, may impair mitochondrial function.

• Reduced ATP generation → fatigue, reduced physical activity, decreased basal metabolic rate.

• Mitochondrial dysfunction linked to weight gain independent of caloric intake.

5️⃣ Dopaminergic Modulation and Physical Activity

• Dopamine D2 antagonism (antipsychotics) reduces motivation and spontaneous physical activity (voluntary movement, non-exercise thermogenesis).

• Decreased physical drive → lower daily energy expenditure.

6️⃣ Alteration of Gut Microbiota

• Animal studies: antipsychotics shift gut microbiome toward obesity-promoting phenotypes (Firmicutes > Bacteroidetes).

• Increased energy harvest from diet, low-grade inflammation.

• Emerging evidence connects microbiota changes with psychiatric symptomatology and metabolic profiles.

7️⃣ Changes in Adipokine Profiles

• Increased leptin levels (due to weight gain) paradoxically drive further weight gain through leptin resistance.

• Reduced adiponectin (anti-inflammatory, insulin-sensitizing adipokine) in patients on SGAs.

• Adipokine imbalance promotes visceral adiposity and metabolic syndrome.

8️⃣ Inflammation and Oxidative Stress

• Psychotropics can increase pro-inflammatory cytokines (IL-6, TNF-α) which promote insulin resistance and contribute to weight gain.

• Chronic low-grade inflammation → metabolic derangements, fatigue, depressive symptoms.

9️⃣ Thyroid Axis Alterations

• Lithium is known to cause hypothyroidism in susceptible individuals.

• Subclinical hypothyroidism → fatigue, weight gain, dyslipidemia.

⚠️ Clinical Implications

🔹 Highest Risk Drugs

🔹 Compounding Factors

• Female gender, PCOS

• Genetic predisposition (MC4R polymorphisms)

• Sedentary lifestyle

• Pre-existing metabolic syndrome

🩺 Management Strategies: Evidence-Based Approaches

1️⃣ Proactive Monitoring

2️⃣ Lifestyle Interventions

• Structured dietary interventions: Mediterranean, low-GI, anti-inflammatory diets

• Exercise: Aerobic + resistance training

• Behavioral activation: Increase spontaneous movement, structured routines

• Sleep hygiene: Circadian alignment to optimize metabolism

3️⃣ Pharmacological Strategies

🧠 Conclusion

Psychiatric medications impact metabolic health via diverse pathways—neurotransmitters, hormones, inflammation, and gut microbiota. Recognizing these mechanisms helps tailor prevention, monitoring, and intervention strategies.

Weight gain and fatigue are not merely side effects—they are markers of whole-body metabolic dysregulation requiring integrated care.

At our clinics, we incorporate psychiatry, metabolic monitoring, lifestyle medicine, and personalized pharmacological strategies to ensure holistic mental health recovery without sacrificing physical well-being.

📍 For consultations in Velachery & Tambaram, Chennai
📞 Call 85951 55808 | 🌐 www.srinivasaiims.com