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Many widely used drugs cause weight gain that—especially in susceptible individuals—may lead to patients becoming overweight or obese. Other drugs predominately influence body fat redistribution through increases in central adiposity, including visceral fat accumulation, and/or subcutaneous fat atrophy (lipodystrophy). Accompanying these changes are increases in insulin resistance, dyslipidemia, metabolic syndrome, and risk for type 2 diabetes (T2DM), non-alcoholic steatohepatitis (NASH), cardiovascular disease, cancer, and even increased mortality. These body weight and metabolic side-effects warrant close monitoring and potentially additional therapies to minimize their health impact, thereby increasing medical costs and contributing to non-compliance, which risks worsening of the underlying condition.

Weight gain is consistently associated with many older agents for the treatment of diabetes and with neuropsychotropic medications, including atypical antipsychotics, antidepressants, and antiepileptic drugs (). For other drug classes, e.g. β-blocking agents, data are less consistent or well-studied. Glucocorticoids are associated with weight gain and lipodystrophy, as are retroviral agents used in the therapy of human immunodeficiency virus (HIV). Also, drugs used to manage lipid disorders, such as MTTP inhibitors and anti-sense apo-B oligonucleotides, are associated with changes in body fat distribution, especially liver lipid accumulation. Unfortunately, the mechanisms behind these effects on body weight and fat distribution are often poorly understood, which hampers identification of high-risk patients for prevention, development of lower risk-drugs, and possible treatments (). In this chapter, drugs affecting body weight, fat distribution, and glucometabolic outcomes will be reviewed, as well as the possible mechanisms contributing to these side effects. Recent studies will be highlighted that have been undertaken to identify predictors of weight gain and metabolic complications, and where possible, options for prevention and therapy will be discussed.

Insulin, sulfonylurea (SU), and thiazolidinediones (TZD) are medications used in the management of diabetes that may cause substantial weight gain when compared to placebo (). Metformin and Dipeptidyl Peptidase-4 (DPP-4) inhibitors are considered to be weight neutral, whereas sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor analogues (GLP1RA) are associated with weight loss on average ().

Insulin causes weight gain by multiple mechanisms (). Sulfonylureas cause weight gain by increasing endogenous insulin levels. Appetite stimulation, sometimes triggered by hypoglycemia and fluctuating glycemia, is probably the most important factor in body fat increase. Defensive snacking in order to prevent hypoglycemia or compensate for it, can be observed in some patients. Poor glycemic control increases metabolic rate and consequently, improving glycemic control decreases metabolism. Improving metabolic control also reduces glycosuria and retention of otherwise lost calories. Finally, the anabolic effects of insulin can increase protein synthesis and inhibit lipolysis and proteolysis, resulting in a gain of lean body mass (,). The weight promoting properties of insulin are dose dependent and are more pronounced in injection regiments that include rapid-acting insulin compared to basal insulin only (). The addition of metformin to insulin therapy, reduces the effects of insulin on body weight by decreasing energy intake (). The weight gain by sulfonylurea is most pronounced in the first months of therapy and then reaches a plateau. In the UKPDS and ADOPT studies a mean weight gain of this therapeutic class is approximately 4 kg during the first year of treatment (,).

Thiazolidinediones also cause a substantial time and dose-dependent weight gain ranging from 1.5 to 4 kg in the first year of treatment (,). The mechanisms by which TZD’s cause weight gain include fluid retention, promotion of lipid storage, and adipogenesis through activation of peroxisome proliferator-activator receptor gamma (PPARg) (,). The fat accumulation is almost uniquely subcutaneous, with stable or even decreasing amounts of visceral fat (). Thiazolidinediones also improve hepatic steatosis and inflammation in patients with non-alcoholic steatohepatitis (NASH), although safety concerns including osteoporosis and fluid retention with pioglitazone hamper their use (,). Newer PPAR drugs for the treatment of NASH are currently being studied in phase 3 trials ().

Hypertension frequently accompanies obesity and T2DM. Therefore, drugs that promote weight gain and other metabolic side effects are of obvious concern in patients with obesity and hypertension ().

The propensity of β-blockers to cause weight gain has been known for years (). Their use is associated with a mean weight gain of 1.2 kg compared to controls, although among β-blockers, variable effects on weight, ranging from no significant change to an increase of 4 kg or more after one year of treatment, have been described. Most weight gain occurs in the first few months, after which no further weight gain is apparent (). Mechanisms whereby β-receptor antagonists are thought to affect body weight include reductions in total energy expenditure through lowering of basal metabolic rate and thermogenic response to meals, and by inhibition of lipolysis in response to adrenergic stimulation (). In addition, β-receptor antagonists can promote fatigue and reductions in patient activity (-). Polymorphisms in human genes involved in catecholamine signal transduction affecting fat cell lipolysis might partly explain individual susceptibility to β-receptor antagonist-induced weight gain (). β-blockers may also selectively promote the accumulation of abdominal fat, which is more sensitive to catecholamines than peripheral fat (). This preponderance of abdominal fat accumulation may be, in part, responsible for the abnormalities related to carbohydrate and lipid metabolism associated with β-adrenergic blockade ().

Several large trials have linked β-receptor antagonists to dysglycemia and new onset diabetes, even without significant weight gain (). In particular, non-vasodilating beta-blockers (atenolol, metoprolol and propranolol) are associated with a worsening of glycemic and lipid parameters. In contrast, vasodilating beta-blockers (nebivolol, labetolol and carvedilol) have more favorable effects on glucose and lipid profiles (). Nebivolol has been shown to induce lipolysis, reduce adipocyte lipid droplet size, and promote thermogenic and mitochondrial genes through a β3 adrenergic receptor affect (). Therefore, selective agents with a vasodilating component such as nebivolol and carvedilol should be prioritized when β-blockers are needed in a population with high risk for metabolic side effects ().

Calcium channel blockers are considered weight neutral and do not show adverse effects on glucose and/or lipid metabolism. However, flunarizine, a calcium channel blocker used in the prophylaxis of migraine, is associated with increased appetite and weight gain up to 4 kg. These properties have been linked to its blocking effects on both the calcium channel receptor and the dopamine receptor (,).

Obesity is two to three times more common among patients with psychiatric disorders than the general population, and individuals who are obese suffer more frequently from psychiatric illnesses than those who are normal weight. Underlying causes of this interaction between obesity and psychiatric disease likely include a clustering of adverse metabolic risk behaviors, such as unhealthy eating and insufficient physical activity, as well as substance abuse that accompany many psychiatric conditions (). But the pathophysiological neural processes that lead to psychiatric diseases also seem to share common brain pathways with those that lead to unwanted weight gain, obesity, metabolic syndrome, and cardiovascular disease risk factors, each of which can influence the risk for the others (). Mounting evidence points to a critical role for two major pathways: inflammatory processes including related alterations of brain functions and chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis (,).

Psychiatric disorders are often characterized by a chronic stimulation of the HPA axis and sustained cortisol elevation, which have been linked with abdominal obesity, hepatic steatosis, insulin resistance, and cardiovascular disease (). Chronic psychosocial stress has also been linked with inflammation and metabolic alterations, including weight gain with a predominance of visceral fat accumulation and insulin resistance (). On the other hand, increased adiposity leads to chronic low-grade activation of inflammatory processes, which have been shown to have a potent role in the pathophysiological brain alterations associated with psychiatric disease (). It is therefore possible that adiposity-driven inflammation contributes to the development of mood disorders and their growing prevalence worldwide.

Medical therapies for depression, mood disorders, and other psychiatric illnesses have been associated with sometimes very large weight gain (). Epidemiologic data show a positive correlation between weight gain and the time exposed to psychotropic medication or the number of different psychotropic drugs used (). However, the variation in mean weight gain is large between the different drug classes and even within the same class. For most psychiatric treatments, no correlation is found with weight gain and original diagnosis or severity of the underlying psychiatric condition, treatment outcome, weight at the onset of the disease or treatment, age, or sex, which impedes prediction of those patients who will or will not have metabolic side effects (). What has been consistently shown is that weight gain in the first month after the start of treatment is a strong predictor of long-term weight gain (). Therefore, weight should be monitored before and shortly after starting a psychotropic drug therapy and a 5% increase above baseline weight after the first month should prompt physicians to reconsider therapeutic options or to initiate weight-controlling strategies (,).

The greatest potential to induce weight gain has been shown with the tricyclic agents’ amitriptyline and nortriptyline. Antidepressant–induced weight gain has been clearly established in the acute and maintenance period of depression therapy and is not related to disease severity. Medications from this drug class are also associated with weight gain when used for other indications, such as neuropathic pain or anxiety. To date, no predisposing factors to weight gain resulting from these drugs has been clearly identified ().

During initial treatment, several selective serotonin reuptake inhibitors (SSRI’s) (citalopram, fluoxetine, sertraline) and serotonin and norepinephrine reuptake inhibitors (SNRI’s) (venlafaxine and duloxetine) are associated with a slight weight loss. However, with chronic therapy many have shown weight gain. Paroxetine is considered to be the SSRI with the greatest long-term weight gain, possibly due to its affinity for the cholinergic receptor (,).

Bupropion, a norepinephrine and dopamine reuptake inhibitor and nicotinic antagonist, reduces appetite and food cravings (). In combination with naltrexone, bupropion is approved as an antiobesity drug in United States of America (USA) and the European Union (EU) ().

In randomized controlled trials, the incidence of significant weight gain (more than 5% of initial body weight) has been described to be as high as 60% of the patients on lithium therapy for bipolar disorder. Risk factors for weight gain are a high baseline weight, younger age, co-administration of antidepressants, and female sex (). The exact mechanism by which lithium exerts these adverse effects on weight is still unknown. Possible mechanisms include a direct effect on hypothalamic centers controlling appetite, increased thirst and increased intake of high caloric drinks, changes in food preference, and its influence on thyroid function with increased incidence of hypothyroidism (,).

The number of individuals in the population receiving antipsychotic drugs is surprisingly high, most commonly for psychosis, although antipsychotic drugs are also widely used to treat other psychiatric conditions like bipolar disorders, attention deficit disorder, and dementia in the elderly (,).

Several major chemical classes of antipsychotic drugs have been developed, mainly the phenothiazines (e.g., chlorpromazine), the butyrophenones (e.g., haloperidol), and the thioxanthines (e.g., flupenthixol). All these “conventional,” or typical, neuroleptics are effective because they are dopamine D2 receptor antagonists, but they all have major neurological side effects (). Therefore, newer drugs, the atypical antipsychotics or second-generation antipsychotics (SGAP), are increasingly replacing the conventional neuroleptics. These atypical antipsychotics are characterized by a combined activity on both the D2 and 5-HT2a receptors. Besides their antagonistic effects on these receptors, they possess diverse pharmacologic interactions with a number of neurotransmitter receptors ().

Up to 80% of patients taking antipsychotic medication experience weight gain that exceeds their ideal body weight by 20% or more (). Weight gain variability is high in between these drugs, which has been ascribed to both a high affinity for the H1-histaminic receptor as well as, to a lesser extent, the α1-adrenergic and 5-HT2c-receptors (). The largest weight gain is consistently associated with olanzapine and clozapine. Weight gain promoting effects of the antipsychotics seem to be more pronounced in people with a normal body weight at baseline and more in women than in men. Weight gain associated with long-term treatment is time- and dose-dependent and can be predicted by weight increases in the first weeks of treatment. Drug-naïve patients gain significantly more weight than patients exposed to antipsychotics in the past and studies in pediatric patients demonstrate greater absolute weight gain in this group than in adults. Patients who have greater treatment-emergent weight gain are more likely to benefit from treatment with antipsychotics (,-).

Although SGAP’s influence food intake by altering neurotransmitter function in the hypothalamus, thus leading to excess caloric consumption, obesity, and insulin resistance (), weight gain is not the only concern for patients taking antipsychotic medication (). SGAP’s can also promote lipogenesis and enhance antilipolytic effects of insulin, thereby favoring lipid accumulation and adipocyte enlargement and inducing insulin resistance (). Metabolic sequela includes glucose dysregulation and an increased risk for developing metabolic syndrome and type 2 diabetes (,). Although an increased prevalence of metabolic syndrome has been reported in drug naïve patients with diverse psychoses, there is a significant association with longer disease duration and with the intake of clozapine in particular (,). In one 5-year study of clozapine-treated patients, 52% experienced one or more episodes of hyperglycemia and 30% were diagnosed as having type 2 diabetes (). Newer SGAP appear to have fewer metabolic side effects (,,,).

The development of diabetes in patients taking antipsychotic has also been reported in patients without significant weight changes. SGAP’s are associated with a marked increase in insulin resistance in muscle, adipose tissue, and liver (), possibly mediated by impaired GLUT-4 and GLUT-5 glucose transporter function (). In addition, a direct impairment of pancreatic β-cell function and decreased insulin secretion has been linked to the affinity of these drugs for the 5HT-1a and 5HT-2 serotonin receptors of the β-cells (). Manifestations of insulin resistance, impaired glucose tolerance, metabolic syndrome (including elevations in triglyceride levels and reductions in HDL cholesterol), and type 2 diabetes contribute to the higher incidence of cardiovascular disease in patients taking these drugs. People with psychosis have a 20% shorter life expectancy than the general population, mainly driven by an increase in cardiovascular disease (,). In view of the high cardiometabolic risk associated with antipsychotic drug use, the American Diabetes Association and American Psychiatric Association (ADA/APA) Consensus Development Conference recommends close monitoring of weight and metabolic and cardiovascular risk factors in all patients taking SGAP’s ().

Many studies have evaluated pharmacological and non-pharmacological approaches to prevent or treat weight gain that accompanies SGAP treatment. Of non-pharmacological interventions, no significant difference was found between individual and group interventions, or cognitive-behavioral versus nutritional counselling. Adherence to the weight management program appears the best prognostic factor for achieved weight loss. To promote therapeutic alliance, weight management programs should be flexible and individualized to the patient’s needs, age and stage of their disease and incorporate daily recreational-based activities. Benefits are thought to be the greatest when delivered as early as possible, before weight gain has occurred ().

Switching to another antipsychotic drug with less potential for weight and cardiometabolic side effects has been endorsed by the ADA/APA consensus guidelines in those with more than 5% weight gain or worsening of their lipid or glycemia parameters, following studies that show benefits of this strategy to limit further weight gain or reduce weight and reverse components of the metabolic syndrome (,) (). For example, use of the SNRI reboxetine may reduce olanzapine-induced weight gain in schizophrenia patients. Weight and metabolic benefits have also been reported by switching to, or the addition of, topiramate, amantadine, fluvoxamine, and orlistat (-). With metformin, attenuation or reduction of weight gain and amelioration of the metabolic side effects of SGAP therapy has been demonstrated, with greater benefits the earlier metformin was started (,). In a rodent study, the addition of metformin and berberine prevented the loss of brown fat induced by olanzapine and was associated with favorable changes in expression of several genes controlling energy expenditure ().

In patients who are obese or with diabetes, glucagon-like protein-1 receptor agonists (GLP-1 RA) demonstrate long-lasting weight loss and benefits on glucose metabolism (,). Growing evidence suggests that patients who are overweight and those with psychosis exhibit similar structural brain changes, cognitive deficits, and central neuropeptide alterations, suggesting an overlap between the pathophysiological pathways of these disorders (). GLP-1 RA’s have been shown to provide neuroprotective effects in cerebral degenerative diseases such as Parkinson’s disease, Huntington’s chorea, and Alzheimer’s dementia (). Liraglutide, a once daily injected GLP-1 RA, reverses SGAP-induced weight gain, impaired glucose tolerance, metabolic side effects and behavioral depression (-).

Mifepristone, a glucocorticoid and progestin receptor antagonist, attenuated increases in weight and reduced the metabolic changes induced by risperidone and olanzapine, suggesting mechanistic involvement of the hypothalamic-pituitary-adrenal axis in the weight and cardiometabolic side effects of antipsychotic medications (). The orally effective selective protein kinase C-β (PKC- β) inhibitor ruboxistaurin, which is used in treatment of diabetes-associated retinopathy and macular edema, attenuates the effects on adipose tissue differentiation by clozapine in rodents. If this is shown to be relevant for humans, it could offer a new target for the prevention of antipsychotic-induced weight gain (). Because of the associations between inflammation, adiposity and psychiatric disease, other therapeutic options being explored to improve psychiatric symptoms without adverse metabolic sequelae include COX-2 selective non- steroidal anti-inflammatory drugs, and monoclonal antibodies against anti TNF-α and Interleukin-6 (,).

Many of the anti-epileptic treatments are associated with weight change. Most prominent are valproate and carbamazepine, inducing weight gain in 71% and 43% of the patients, respectively. Pregabalin and gabapentin can also induce weight gain and are of particular importance since they are used more and more in the treatment of neuropathic pain, including in patients with diabetes. Weight neutral anti-epileptic drugs include lamotrigine, levetiracetam and phenytoin. Some others are associated with weight loss, including felbamate, topiramate, and zonisamide (). Weight-inducing effects of valproate are thought to result from interactions with appetite-regulating neuropeptides and cytokines within the hypothalamus as well as effects on energy expenditure (). Greater weight gain is associated with longer duration of treatment with valproate, although most weight gain is observed within the first year. Specific categories of patients shown to be more susceptible to weight gain with this medication include women (vs. men), post-pubertal adolescents (vs. younger children), and those who are overweight before treatment begins. On the other hand, weight gain is not related to valproate dosage or serum levels ().

Peripheral actions are thought to mediate valproates adverse effects on glucose and lipid metabolism that contribute to weight-independent worsening of insulin resistance and risk for type 2 diabetes. Directs effects in adipose tissue have been shown to increase leptin resistance, decrease adiponectin levels, as well as increase free fatty acids, all resulting in insulin resistance (). On the other hand, valproic acid is associated with β-cell dysfunction and impaired insulin secretion by increasing oxidative stress, and direct inhibition of the GLUT-1 transporter, thereby hampering insulin secretion in an insulin resistant state, promoting hyperglycemia and type 2 diabetes (-). Besides the increased risk for hyperglycemia and type 2 diabetes, an increased risk of other features of the metabolic syndrome (e.g., dyslipidemia) as well as endothelial dysfunction has been demonstrated. It has additionally been reported that up to 60% of the patients taking valproate also develop non-alcoholic steatohepatitis, further contributing to insulin resistance, chronic inflammation, and increased risk for cardiovascular disease ().

With the other anticonvulsants, weight gain can be considerable in susceptible patients (). However, in contrast to valproate, metabolic side effects accompanying use of carbamazepine, pregabalin and gabapentin are thought to be secondary to the induced weight gain rather than weight-independent mechanisms (). On the other hand, topiramate and zonisamide have been shown to decrease body weight, even when studied in populations with obesity and overweight without any seizure history. Adding topiramate to another antiepileptic, antipsychotic or antidepressant drug, or changing anticonvulsant therapy for topiramate or zonisamide can help prevent or treat weight gain that accompanies psychiatric or anticonvulsant therapy (,). In the USA, the combination therapy topiramate/phentermine is approved as an antiobesity drug ().

Although weight gain is considered a common side-effect of long-term treatment with glucocorticoids, prospective studies examining weight gain are scarce. Self-reported data in patients using chronic corticoid therapy show substantial weight gain in up to 70% of all patients (). The weight gain associated with glucocorticoid therapy can be massive with over 10 kg increases in approximately 20% of patients in their first treatment year of treatment. The risk of weight gain with glucocorticoids is dose dependent and significantly increases with intakes above the equivalent of oral or parenteral 5 mg prednisone per day. Inhaled corticosteroids and single epidural steroid injections have no effect on body weight. Glucocorticoids may induce an increase in food intake and dietary preference for high-caloric, high-fat ‘comfort foods’ through changes in the activity of AMP-activated protein kinase in the hypothalamus (-). Glucocorticoids decrease thermogenesis and uncoupling protein 1 (UCP-1) expression in brown adipose tissue, thereby influencing metabolic rate (). Chronic glucocorticoid therapy or a state of chronic hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis is associated with activation of the endocannabinoid (eCB) system, which is a potent regulator of food intake and decreases energy expenditure ().

Glucocorticoids also affect body fat distribution by increasing visceral fat mass, thereby increasing insulin resistance and the risk for impaired glucose tolerance, diabetes and cardiovascular disease (). Although the mechanisms for this are not completely understood, glucocorticoids acutely stimulate lipolysis through the activation of hormone-sensitive lipase and an increased catecholamine responsiveness. When this disproportionately affects fat stores in the extremities, it can lead to loss of these depots, or lipodystrophy, the risk of which has been reported to be higher among females and younger patients and increases with a higher baseline body mass index (). On the other hand, during chronic administration or exposure to high endogenous plasma corticoid concentration such as in Cushing’s syndrome, they promote both adipocyte hypertrophy by increasing synthesis and storage of lipids and adipose tissue hyperplasia by increasing differentiation of preadipocytes to mature adipocytes. Visceral adipose tissue has a higher glucocorticoid receptor density as compared with other fat depots, which might favor enhanced expansion of visceral adipose tissue (). These differential effects on visceral and subcutaneous fat may be mediated by differential regulation of key metabolic genes including lipoprotein lipase, 11-beta-hydroxysteroid-dehydrogenase-1 (11β-HSD-1) and UCP-1 ().