In recent decades, obesity has assumed the character of a non‑communicable pandemic. According to the World Health Organization, in 2016, more than 1.9 billion adults were overweight, of whom over 650 million had obesity [1]. In the Russian Federation, the proportion of individuals with overweight was 62.0%, and with obesity — 26.2% [1]. Projections indicate that by 2030, up to 60% of the world’s population may be overweight or obese if current trends continue [1]. The prevalence of obesity among men in Russia reaches 30%, and among women — 39.5%, with abdominal obesity registered in 30.9% of men and 55.1% of women [2].

Alongside well‑known factors (physical inactivity, hypercaloric nutrition, genetic predisposition), iatrogenic factors contribute substantially to the increasing prevalence of overweight. According to meta‑analyses, up to 20–25% of newly diagnosed obesity cases in adults may be associated with the use of medications prescribed for chronic diseases [3, 4]. In the United States, about 50% of adults take at least one medication over a 30‑day period, and many of these have the potential to induce weight gain [5].

Drug‑induced weight gain (DIWG) is often regarded as a "silent" adverse effect that is either underestimated by clinicians or accepted as a trade‑off for controlling the primary disease (e.g., managing psychotic symptoms or achieving target glucose levels). However, weight gain during pharmacotherapy leads to poor adherence, increased risk of cardiovascular complications, progression of hepatic steatosis, and reduced quality of life [5]. In the clinical guidelines of the Ministry of Health of the Russian Federation (2024), iatrogenic obesity is classified as a distinct category (ICD‑10 code E66.1) [1], underscoring the relevance of this issue.

The mechanisms of DIWG are complex and multifactorial. The key pathogenetic links include [6, 7]:

1. Central effects. Many drugs act on hypothalamic centers regulating hunger and satiety.

2. Endocrine disturbances.

3. Alterations in energy balance.

4. Role of microbiota and genetic predisposition.

5. Impact on eating behavior and thirst.

Antipsychotics. The most extensively studied group is atypical antipsychotics (second‑generation). The risk of weight gain varies by agent: highest for clozapine and olanzapine (gain of 4–10 kg over the first 6–12 months, with 80% of patients gaining more than 20% of baseline weight) [8, 25]; moderate for risperidone and quetiapine (gain of 2–4 kg) [26]; minimal for aripiprazole, ziprasidone, amisulpride, asenapine, iloperidone, lurasidone, and paliperidone, which are associated with the lowest metabolic risk [27, 28].

Pathogenesis: potent H1 and 5‑HT2C receptor antagonism, along with effects on AMP‑activated protein kinase in adipocytes. Notably, in antipsychotic‑naïve patients, weight gain may be more pronounced, especially in children and adolescents [29]. Weight gain during the first month of treatment is a strong predictor of long‑term weight gain, enabling timely intervention [30].

Furthermore, antipsychotics are associated with the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome even without significant weight gain, indicating direct effects on pancreatic β‑cells and peripheral insulin sensitivity [31, 32]. The prevalence of metabolic syndrome in patients with schizophrenia reaches 32%, and the risk of T2DM is 2–3 times higher than in the general population [33].

Antidepressants and mood stabilizers. Tricyclic antidepressants (amitriptyline, nortriptyline) and monoamine oxidase inhibitors are associated with significant weight gain — on average 2–4 kg, and in some patients up to 9 kg [34, 35]. Among selective serotonin reuptake inhibitors (SSRIs), paroxetine is the most unfavorable (gain of 1.7–3.6 kg); citalopram is also associated with weight gain, while fluoxetine and sertraline are relatively neutral in the long term [36, 37]. Bupropion, conversely, consistently demonstrates weight loss (0.4–2.4 kg) and may be considered a metabolically favorable alternative, particularly in patients with obesity [38, 39]. In combination with naltrexone, bupropion is registered as an anti‑obesity medication [40].

Lithium and valproic acid also promote weight gain. In 60% of patients on lithium, a weight gain of more than 5% of baseline is observed [41]. Valproate is characterized by the development of insulin resistance and hyperinsulinemia, related to direct action on pancreatic β‑cells (GABA‑mediated enhancement of insulin secretion), increased leptin levels, and decreased adiponectin [14, 42]. Non‑alcoholic fatty liver disease develops in 60% of patients receiving valproate [43].

Antihyperglycemic agents. Paradoxically, drugs designed to control diabetes often exacerbate obesity. Insulin causes dose‑dependent weight gain via several mechanisms: appetite stimulation, especially during hypoglycemic episodes, reduced glucosuria, and anabolic action (increasing muscle and fat mass) [44, 45]. Weight gain with insulin may range from 0.4 to 4.8 kg, and is more pronounced with rapid‑acting insulins compared with basal insulins [46]. Insulin detemir has a relative weight‑reducing effect, the mechanism of which is not fully understood [47].

Sulfonylureas (glibenclamide, glimepiride) also cause hyperinsulinemia and weight gain: in the UKPDS and ADOPT trials, the gain was approximately 4 kg in the first year of treatment [48, 49]. Gliclazide and glimepiride are associated with less weight gain than older sulfonylureas [50].

Thiazolidinediones (pioglitazone, rosiglitazone) increase subcutaneous fat mass due to preadipocyte differentiation, but may reduce visceral fat content and improve hepatic steatosis [51, 52]. Weight gain is 1.5–4 kg in the first year.

In contrast to these classes, metformin is associated with weight loss (1–2.9 kg) [3, 53]. Dipeptidyl peptidase‑4 (DPP‑4) inhibitors (sitagliptin, saxagliptin, linagliptin) are neutral or associated with slight weight loss [54]. GLP‑1 receptor agonists (exenatide, liraglutide, semaglutide) and SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) provide sustained weight loss, making them preferred in patients with obesity and T2DM [3, 55, 56].

Glucocorticoids. Systemic (and, to a lesser extent, inhaled) glucocorticoid use leads to iatrogenic Cushing’s syndrome. According to population‑based studies, 70% of patients on long‑term glucocorticoid therapy experience significant weight gain, and 20% gain more than 10 kg in the first year of treatment [57, 58]. Prednisolone is associated with a gain of 1.7–5.8 kg, prednisone — 1.5–4.4 kg, cortisone — 1.5–8.4 kg [59, 60].

The mechanism includes appetite stimulation through altered AMP‑activated protein kinase activity in the hypothalamus, increased preference for fatty foods, activation of the endocannabinoid system in the liver and adipose tissue (via cannabinoid receptor type 1), and induction of insulin resistance [11, 61, 62]. Notably, even low doses of prednisone (5–10 mg/day) can cause significant metabolic disturbances [63].

Antihypertensive agents. β‑blockers (especially non‑selective ones such as propranolol and atenolol) reduce basal metabolic rate (by 4–9%), decrease exercise tolerance, and suppress lipolysis, leading to an average weight gain of 1–2 kg [15, 64, 65]. In the GEMINI trial, patients on metoprolol gained 0.6 kg over 6 months, whereas weight did not change with carvedilol [66]. Selective β‑blockers with vasodilating properties (carvedilol, nebivolol) have a more favorable metabolic profile and do not worsen insulin sensitivity [67].

Diuretics (hydrochlorothiazide, chlorthalidone) and calcium channel blockers (amlodipine) are considered neutral or associated with slight weight loss (0.4–2.7 kg) [68, 69]. Angiotensin‑converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) do not affect weight or promote modest weight loss, while improving insulin sensitivity [70, 71]. Direct renin inhibitors (aliskiren) are also metabolically neutral [72].

Antiepileptic drugs and other groups. DIWG is also predisposed by antiepileptic drugs. Valproate causes weight gain in 71% of patients, carbamazepine in 43%, and gabapentin and pregabalin also contribute to weight gain, especially with long‑term use [73, 74]. Valproate is associated with the development of insulin resistance independent of the degree of weight gain and with a high risk of non‑alcoholic fatty liver disease [14, 43]. Topiramate and zonisamide, in contrast, are associated with weight loss, which is used in combination therapy for obesity (phentermine/topiramate) [75, 76].

Among other groups: first‑generation antihistamines (diphenhydramine, hydroxyzine) may cause weight gain via H1 receptor blockade; protease inhibitors (antiretroviral therapy) induce lipodystrophy and visceral obesity [77].

A major problem is that clinicians often delay intervention until the patient's body mass index reaches critical values (class II–III obesity). According to Russian clinical guidelines, the diagnosis of obesity (code E66) should be based on measurement of body mass index (BMI) and waist circumference (WC) [1]. Abdominal obesity (WC ≥94 cm in men and ≥80 cm in women) is an independent risk factor for cardiovascular disease and requires active intervention [1, 2]. In the Russian population, the combination of obesity with hypertension and carbohydrate metabolism disorders significantly worsens prognosis [2].

The weight management strategy in the context of DIWG should include three stages:

1. Prevention (primary and secondary)

2. Therapy modification. When significant weight gain occurs (more than 5–7% from baseline), pharmacotherapy revision is appropriate [78, 80]:

3. Non‑pharmacological interventions. Lifestyle modification remains a cornerstone; however, the effectiveness of dietary restrictions and physical activity during treatment with centrally acting drugs may be reduced. Structured programs involving dietitians and physiotherapists are needed. According to clinical guidelines, a 5–10% weight loss over 3–6 months reduces health risks and improves the course of comorbid diseases [1]. In patients with BMI ≥35 kg/m² and severe complications (T2DM, obstructive sleep apnea syndrome), bariatric surgery may be considered [1, 92]. In patients with psychotic disorders and obesity, combined programs (diet + physical activity) provide an average weight loss of up to 3.3 kg [93].

Effective management of drug‑induced weight gain (DIWG) is impossible without implementing patient‑centered principles, which transform the traditional "doctor‑patient" model into a partnership. This approach is based on the following key elements:

Integrating these principles into clinical practice not only enables more effective weight management but also strengthens the therapeutic alliance, which is critically important for the treatment of chronic diseases.

Drug‑induced weight gain is an inevitable consequence of therapy for many chronic diseases and requires a systematic approach. Ignoring this adverse effect negates the long‑term benefits of treatment, contributing to the cardiometabolic continuum. Personalized drug selection considering metabolic profile, early monitoring (BMI, waist circumference, glucose, lipids), and multidisciplinary collaboration (psychiatrist, endocrinologist, cardiologist) are the foundations for minimizing iatrogenic risks and improving patient adherence to therapy. The introduction into clinical practice of modern metabolically neutral and weight‑reducing drugs (GLP‑1 receptor agonists, SGLT2 inhibitors, metformin) opens new possibilities for weight management in patients who must take medications with weight‑gain potential.