REGISTRO DOI: 10.5281/zenodo.8083720
Sandro Pinheiro da Costa1
Pedro Julien Salvarani Borges2
Laís Silva Quintão3
Adelcio Machado dos Santos4
Larissa Silva Gradil Costa5
Matheus Pereira Cavalcante6
Lara Vento Moreira Lima7
Carlos Alberto Feitosa dos Santos8
Alisson Lopes Costa9
Rodrigo Daniel Zanoni10
Abstract
Currently, the search for rapid weight loss has provided elaborations of different masterful formulations with various associated substances, among which antidepressants stand out. Recent years have seen the approval of a number of new anti-obesity drugs. Most of these influence hypothalamic appetite pathways via dopaminergic and serotonergic signaling. Combination therapies, allowing lower doses to minimize potential off-target effects. In this sense, it is understood that the use of antidepressants in slimming formulations is effective in reducing the symptoms of bulimia and treating the associated mental disorders, however these associations are alarming and may lead to risks of abuse and chemical dependence, adverse reactions and pharmacological interactions with the other substances in the same formula.
Keywords: Antidepressants; Obesity; Combined Therapy.
Resumo
Atualmente, a busca pela rápida perda de peso tem proporcionado a elaboração de diferentes formulações magistrais com diversas substâncias associadas, dentre as quais se destacam os antidepressivos. Nos últimos anos, foram aprovados vários novos medicamentos anti-obesidade. A maioria destes influencia as vias hipotalâmicas do apetite via sinalização dopaminérgica e serotoninérgica. Terapias combinadas, permitindo doses mais baixas para minimizar o potencial efeito fora do alvo. Nesse sentido, entende-se que o uso de antidepressivos em formulações emagrecedoras é eficaz na redução dos sintomas da bulimia e no tratamento dos transtornos mentais associados, porém essas associações são alarmantes e podem levar a riscos de abuso e dependência química, reações adversas e farmacológicas interações com as outras substâncias na mesma fórmula.
Palavra-chave: Antidepressivos; Obesidade; Terapia Combinada.
Resumen
Actualmente, la búsqueda de una rápida pérdida de peso ha llevado al desarrollo de diferentes formulaciones magistrales con diversas sustancias asociadas, entre las que destacan los antidepresivos. En los últimos años, se han aprobado varios medicamentos nuevos contra la obesidad. La mayoría de estos influyen en las vías hipotalámicas del apetito a través de la señalización dopaminérgica y serotoninérgica. Terapias combinadas, que permiten dosis más bajas para minimizar el posible efecto fuera del objetivo. En este sentido, se entiende que el uso de antidepresivos en formulaciones adelgazantes es eficaz para reducir los síntomas de la bulimia y en el tratamiento de los trastornos mentales asociados, pero estas asociaciones son alarmantes y pueden conllevar riesgos de abuso y dependencia química, efectos adversos y reacciones farmacológicas interacciones con las demás sustancias de la misma fórmula.
Palabras clave: Antidepresivos; Obesidad; Terapia Combinada.
1 Introduction
The controlled substances used in compounding pharmacies are pre-established by the National Health Surveillance Agency (ANVISA) by Ordinance SVS/MS nº 344/1998 (BRASIL, 1998), where pharmacological classes of interest to health are discriminated, as they act in the system central nervous system, such as: antidepressants, anxiolytics, antipsychotics, narcotic analgesics, anorectics, among others. The Report of the International Board of Narcotics Control (INCB) that occurred in the year 2007 showed that Brazil has a high consumption of anorectic in the treatment of formulations for slimming. This consumption has been growing intrinsically (UNITED NATIONS ORGANIZATION, 2008).
Pharmacies authorized to manipulate these substances exhibit certain dangers, handling must be strictly controlled so that there is no quality deviation in the process of handling substances used in the treatment of mood disorders (YANO & AURICCHIO, 2005). Mood disorders are psychiatric disorders in which they exhibit changes in mood, these deviations can be given by the use of antidepressant drugs (MANUAL, 2002). The mechanism of action of antidepressant drugs occurs in the increase of free neurotransmitters of serotonin, noradrenaline and/or dopamine in the synaptic cleft, being selectively or competitively through their reuptake by enzymatic inhibition by their degradation called monoamine oxidase inhibitors (VISMARI, ALVES & PALERMO , 2008).
In recent decades, psychopharmacology has developed rapidly, with the emergence of new antidepressant agents with different pharmacological characteristics and adverse effects (MORENO, MORENO & SOARES, 1998; GARTLEHNER et al., 2008). Depression is currently one of the most frequently encountered disorders, in which it is defined by a continuous depressive mood, in which the individual with it presents symptoms such as: feelings of sadness, hopelessness, emptiness, helplessness, loss of interest or pleasure, excessive guilt, much commonly accompanied by changes in appetite and weight, insomnia, fatigue, psychomotor agitation, among other symptoms. These individuals often present actions that harm their well-being and physical integrity, such as a suicide attempt (GUIMARÃES, 2010; WANNMACHER, 2004).
Currently, with the excessive search for weight loss, where there is a high risk of morbidity and mortality, in which obesity is a serious public health problem, its prevalence is growing at epidemic levels (FARIA et al., 2010; LOZANO & GONZALES, 2010).
With the increasing number of individuals with an aesthetic purpose, pharmacological treatment is becoming increasingly common, in which the class of appetite suppressants stands out, very commonly used in masterful formulations for weight loss such as fluoxetine and sertraline ( selective serotonin reuptake inhibitor antidepressants – SSRI), this type of drug is used in the adjuvant intervention to anti-obesity treatment (LI et al., 2005).
Antidepressant drugs are often prescribed in association with other drugs in the same formulation, such as anxiolytics, diuretics, laxatives, hormones, among others. These drug combinations for weight control are still not well studied, and the efficacy and safety established in these combinations have not yet been thoroughly evaluated. The association of different substances in the same formulation indicated in the treatment of weight loss is commonly used and this type of association is contraindicated for long-term treatment. In view of this, Ministry of Health Ordinance number 344/1998, previously cited, together with the Federal Councils of Medicine and Pharmacy, repudiate the prescription of various amphetamine-type drugs with other controlled-use medications (BRASIL, 1998).
Therefore, considering the pharmacological importance, quality of life, efficacy and safety in the lives of patients aiming to lose weight, who have or do not have eating disorders, with aesthetic pretensions, this present work aims to analyze the studies that describe the effect of antidepressants on weight changes body, that is, its influence on weight gain or loss for its users.
2 Development
2.1 Methodology
This study is bibliographic in nature, based on information collected from articles published in indexed scientific journals, books and postgraduate theses. The following databases were used: Medical Literature Analysis and Retrieval System Online (Medline); Latin American and Caribbean Literature in Health Sciences (LILACS); Scientific Electronic Library Online (SciElo) and Scopus; Web of Science (ISI).
The research period included studies published between January 2015 and September 2023, in Portuguese, English and Spanish. The review was carried out from January to June 2023, with data from 1965 to 2015 being found. This is a qualitative study. “Obesity epidemiology”.
The use of the articles was analyzed according to the theme of the study, where those that did not present specific data about the research were rejected. Articles based on pharmacological, toxicological and pharmaceutical studies were obtained. Of the 147 articles analyzed, 116 were used because they showed essential data for carrying out the bibliographic survey, and 31 were excluded from the research because they did not present specific content for carrying out the work.
2.2 Epidemiology of obesity
Currently, 600 million adults, that is, 13% of the world’s population, are obese, with a body mass index (BMI) of ≤ 30 kg / m² (WHO, 2014). The prospects are that 20% of adults will be obese by 2030 (WHITAKER et al., 1997). Obesity has become a global public health problem and with that, strategies for the control and prevention of this disease are indispensable. The prevalence in Brazilian adults in 2012 was 51.0% for overweight and 17.4% for obesity (MALTA et al, 2014). Nutritional status is directly linked to the environment, individual intervention may not be effective in preventing or reducing obesity (CUMMINS & MACINTYRE, 2006; PAPAS, et al 2007; TRASANDE et al., 2009).
In general, great benefits for health are derived from interventions on a population scale (ROSE, 1992). Factors such as the social, cultural, political and physical environment that influence diet in order to reduce the prevalence of obesity (WHO, 1999). In Brazil, the National Food and Nutrition Policy (BRASIL, 2012) promotes healthy diets and active lifestyles, and defines it as a set of actions to ensure environments that support these practices, such as the Global Strategy for Diet, Physical Activity and Health (WHO, 2004).
In Brazil, in recent years, there have been improvements in health promotion, such as the regulation of the sale of unhealthy foods, the promotion of local agricultural production and professional guidance for free physical activities in several cities. However, the prevalence of obesity has been increasing, additional population policies are needed to control this epidemic (SCHMIDT et al., 2011). The WHO estimates that, in 2015, approximately 2.3 billion adults will be overweight and, of these, 700 million will be obese (WHO, 2015).
2.3 Obesity Assessment Method
There are different methods for evaluating obesity, some are more used and practical, among them the determination of height and weight, which are expressed in body mass index (BMI), being possible to generate the degree of excess weight, or abdominal circumference, making it possible to determine regional body fat, such as skinfolds (WHO, 2004). BMI classification and risk for comorbidities are shown in Table 1.
Table 1: Classification of obesity by BMI and risk of comorbidities
| IMC (kg/m²) | Classification | risk of comorbidities |
| < 18,5 | Low weight | Low |
| 18,5 a 24,9 | healthy weight | Average |
| 25 a 29,9 | pre-obesity | Increased |
| 30 a 34,9 | class I obesity | Moderate |
| 35 a 39,9 | class II obesity | Severe |
| ≤ 40 | class III obesity | very severe |
Source: Adapted from WHO (2004)
The main diseases involved as comorbidities in obesity are cardiovascular disease, hypertension, dyslipidemia, diabetes mellitus, glucose intolerance, insulin resistance, metabolic syndrome, lung problems, sleep apnea, osteoarthritis, gout, hyperuricemia and some types of cancer, mainly gastrointestinal and hormone-dependent disorders (WHO, 2004).
2.4 Physiological Mechanisms of Obesity
The amount of fat in the body called adiposity is not, as has been thought, just a passive result of bad habits or other factors. On the contrary, it is also regulated as part of the process of energy homeostasis, a process by which energy intake (food consumption) is compared with energy expenditure and the size of the body’s fat mass. The main organ that regulates this system is the brain, although multiple organs participate in the process (BEGLINGER et al, 2001; MUURAHAINEN et al, 1991).
The pathways by which signals related to fat mass are integrated with signals from the gastrointestinal system to control all aspects of energy homeostasis. Adiposity signals are connected through central autonomic pathways to centers that process satiety signals. Reduced input of adiposity signals (eg, after weight loss) increases meal size, reducing the brain’s response to satiety signals (SCHWARTZ et al, 2000). Thus, it has been demonstrating how the circulation of signals related to the size of the fat mass (signs of adiposity) occurs and their integration with the signals from the gastrointestinal system (signals of satiety) to control the signals of adiposity. Energy first enters the brain at the level of the hypothalamus. Neural signals from the gastrointestinal system and the liver provide information about the food being consumed, for example, the taste of the food, how much the stomach is distended, and the chemical composition of the food. These satiety signals are sent to the brain. The brain responds to hormonal signals through integrated neuropeptide pathways, leading to a series of outputs that are directly related to energy homeostasis. These include: the neuroendocrine activation of the pituitary gland, the motor behavior (feeding, exercise, etc) and the autonomic activity (MUURAHAINEN et al, 1991).
In recent years it has become apparent that the autonomic nervous system has a much greater impact than previously thought, particularly on many fundamental processes of metabolism, including lipolysis, secretion of insulin and glucagon from the pancreas, and synthesis and secretion. of glucose in the liver. It is important to note that while energy expenditure tends to decline with age, mainly because of inactivity and extreme physical exertion, energy expenditure does not tend to decline to the same extent, for a number of reasons, including sleeping habits. life. Thus, there is a tendency over time for body weight to increase (POLONSKY, GIVEN & VAN CAUTER, 1988).
2.5 Therapeutic implications
Current understanding of the therapeutic implications suggest that those therapies that target the “downstream” leptin and insulin receptors in the brain are likely to be particularly successful in producing weight loss. Leptin and insulin, when entering the brain more specifically in the arcuate nucleus, activate catabolic pathways (involving, for example, the activation of serotonin and noradrenaline), inhibiting anabolic pathways. There is overwhelming evidence that resistance to leptin and insulin in the transport system across the blood-brain barrier is partially responsible for obesity in many individuals.
In summary, the neuroendocrine control system over energy homeostasis is complex, with multiple possible intervention points. The placebo effect is large in the treatment of obesity, and any therapy should cause greater weight loss than placebo. Most treatments that have been tried over the years produce a rapid decrease in body weight before a plateau. This plateau of weight loss occurs because as body weight decreases, so does the metabolic rate decrease and there are levels of adiposity signals back to the brain, which tends to cause increased reduced food intake (COMUZZIE & ALLISON , 1998).
Due to the complexity of the energy control system and the various redundancies within it, therapeutic strategies that intervene at only one point in the system will be less effective than those aimed at two or more processes. Thus, for example, targeting satiety, with cholecystokinin (CCQ), or targeting adiposity signaling, through insulin or leptin. However, animal studies have shown that combinations of very low doses of CCQ plus insulin or leptin in both satiety and adiposity treatment have a large effect on body weight reduction. It is noteworthy that the drugs currently used in Brazil and Europe, such as orlistat, comprise a single process (absorption), while sibutramine acts on two processes (satiety and energy expenditure) (BEGLINGER et al, 2001).
2.6 Pharmacology for Weight Loss
There are several factors that influence weight loss such as the environment, eating behavior, lifestyle and genetics. Obesity is the result of an energy imbalance sustained over several years, and treatments for obesity aim to reverse this imbalance. Consequently, all anti-obesity agents have at least one of the following effects: reducing food intake or nutrient absorption or increasing rest or activity-related energy expenditure. Appetite reduction is the main weight loss mechanism for most current agents. The arcuate nucleus of the hypothalamus plays a critical role in appetite regulation. It contains two populations of key neurons, which project to other hypothalamic nuclei and distant brain regions to alter eating behavior through agouti peptide (AgRP) related neuropeptide Y (NPY), which increase food intake, and the others co-expressed by pro-opiomelanocortin (POMC) and cocaine-regulated transcript (CART), which inhibit food intake. Because of the semipermeable blood-brain barrier in this region, peripheral signals indicative of energy, including glucose, insulin, leptin, a number of gut-derived factors, including glucagon-like peptide-1 (GLP-1), peptides YY (PYY ), oxyntomodulin and ghrelin can directly interact with these neurons and influence eating behavior (SUZUKI et al., 2010).
Neuronal POMC activity is also modulated by dopaminergic and serotonergic signaling from other brain regions and is therefore affected by a number of central nervous system (CNS) drugs that act on these neurotransmitters. 2015; ROEPKE et al., 2012; CHU et al., 2014).
However, appetite is regulated not only by physiological energy status, but also by environmental and emotional issues, such as the sight and smell of food. These reward-associated stimuli are integrated by the mesocorticolimbic reward system, with dopaminergic neurons originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens and prefrontal cortex, where they influence eating behavior. .
Signaling modulation in the dopaminergic reward system is also suggested as an additional mechanism for the action of some appetite suppressants (KIM, QUINN & SPANSWICK, 2009; MIETLICKI-BAASE et al., 2013). MTD (brown fat) expresses high levels of uncoupling protein-1, which uncouples substrate utilization from mitochondrial ATP production, causing energy waste (BUSIELLO, SAVARESE & LOMBARDI, 2015).
A variety of peripheral factors can directly increase MTD activity, such as catecholamines, glucagon, thyroid hormone and fibroblast growth factor 21 (SCHULZ & TSENG, 2013), raising the possibility of pharmacological manipulation. Furthermore, AgRP/NPY and POMC neurons can control the sympathetic innervation of MTDs, revealing a central role for this system in several aspects of energy homeostasis. This is relevant from a therapeutic point of view, as compensatory physiological and behavioral responses to weight limitation. (BILLINGTON et al., 1991; SHI et al., 2013; MORGAN et al., 2015).
3 Results and Discussion
Preventive measures to tackle environmental determinants of obesity at the population level are essential, but so far they have not been sufficiently applied to reverse the trend. Effective treatments for individuals are therefore urgently needed. Lifestyle interventions can be effective, but inadequate responses are seen in a significant proportion of patients. Despite the gold standard program used in the Look Ahead Trial, only 46% of patients achieved 5% weight loss (WADDEN et al., 2011). Furthermore, weight regain is common when the intensive aspect of lifestyle programs ends (Price et al., 2013). Bariatric surgery leads to sustained weight loss and long-term health benefits (SJOSTROM et al., 2012), but carries with it a small but significant postoperative mortality rate and a risk of long-term complications, therefore , there are often incentives for more effective pharmacological treatments that help weight loss (PRICE et al., 2013).
With regard to drugs for the treatment of obesity, currently the market does not have many drugs. These medications can be divided into three categories. The first is the group of drugs that suppress appetite (for example, sibutramine); the second is the group of drugs that interfere with digestion (for example, orlistat), and the third category is a non-homogeneous group of drugs that are effectively used for indications other than weight loss, but with a concomitant effect on weight loss. Such drugs are, for example, incretins used in the treatment of diabetes (eg exenatide, liraglutide), anti-epileptic drugs (eg topiramate) and antidepressants (eg fluoxetine, sertraline) (BARBER, BEGBIE & LEVY , 2010). Table 2 shows the list of drugs authorized for the treatment of obesity.
Table 2: Characteristics of currently licensed pharmacologic agents for long-term weight loss.
| Medicine | Concentration | Mechanism of action | Adverse effects | Contraindications |
| Orlistat (xenical) | 120 mg three times a day (just before, during or after meals) | Intestinal lipase inhibitor | Common/mild: oily stools, malabsorption of fat-soluble vitamins (multivitamins are recommended). | Malabsorption syndromes, cholestasis, pregnancy / breastfeeding. |
| Lorcaserin (belviq) | 10 mg twice a day | 5-ht2c agonist | Rare/serious: may reduce the absorption of some drugs such as cyclosporine and some antiretrovirals, cholelithiasis | Ssris/snris and related drugs, coexisting congestive heart failure, valvular heart disease, pregnancy |
| Phentermine/topiramate (qsymia) | Starting dose is 3.75 mg / 23 mg per day, standard maintenance dose 7.5 mg / 46 mg per day, maximum dose 15 mg / 92 mg per day | Norepinephrine + dopamine release / gaba modulation | Common/mild: headache, nausea, dry mouth, dizziness, fatigue, constipation. | Pregnancy, recent or unstable cardiovascular disease, glaucoma, hyperthyroidism, mao inhibitors or sympathomimetic amines. |
| Bupropion/naltrexone (contrave, mysimba) | 16 mg / 180 mg twice daily for 4 weeks | Dopamine + norepinephrine reuptake inhibitor / opioid antagonist | Rare/serious: serotonin syndrome, valvular heart disease, cognitive impairment, priapism, hypoglycaemia. | Seizures, uncontrolled hypertension, anorexia nervosa, alcohol or opiate withdrawal, bipolar disorder, end-stage renal disease, mao inhibitors. |
| Liraglutide (saxenda) | 3 mg daily by subcutaneous injection for 5 weeks | Glp-1 receptor agonist | Mild common/: paraesthesia, dizziness, taste disturbances, insomnia, constipation, dry mouth. | Medullary thyroid carcinoma, multiple endocrine neoplasia, gastroparesis, pregnancy. |
In the history of anti-obesity drug treatment, drugs that affect the central nervous system have been the most promising and the most disappointing. Amphetamines approved in 1937 were followed by reports of addiction. And others such as fenfluramine which was withdrawn after reports of heart valve disease, another drug also withdrawn was rimonabant due to severe depression and frequent suicidal thoughts (LESSES & MYERSON, 1938).
Fluoxetine is an antidepressant drug from the group of selective serotonin reuptake inhibitors. Depression is strongly associated with obesity and many drugs used to treat depression. Long-term studies with fluoxetine showed significant weight loss, however, this drug is still mainly indicated for depressive disorders. Fluxetine’s mechanism for weight loss is associated with the increased energy expenditure it can provide (WISE, 1992). Some studies also attribute this effect to sertraline, an antidepressant drug belonging to the group of selective serotonin reuptake inhibitors. Both sertraline and fluoxetine have been shown to be effective in the therapy of overweight patients with binge eating disorder (LEOMBRUNI et al., 2008).
Depression is a potentially fatal disorder that affects about 20% of the world’s population, occurs from childhood to late life and has a strong impact on socioeconomic status, if left untreated it can be fatal (BONDY et al., 2002). According to the World Health Organization depression would be a second major global burden in terms of severity of illness and disability (MANJIT et al., 2001; NESTLER et al., 2002).
Depression is associated with many comorbid conditions, such as cognitive dysfunction, hypertension, diabetes, obesity and cardiovascular complications (SCHULZ et al., 2000; ABRAMSON et al., 2001). Depression and obesity have long been recognized as major public health problems in young people. Data from the National Health and Nutrition Survey Exam, showed that about 17% of young people aged 2 to 19 years are overweight (OGDEN et al., 2006), which is notably a higher rate compared to only 5% of a few decades ago. Several reports have suggested the severity of depression associated with obesity. The exact mechanism of how obesity increases the risk of depression remains to be identified (SHARMA & FULTON, 2012).
Even though obesity and depression are recognized to be separate health problems of a physical and emotional nature, respectively (FAITH et al., 2002), they share some common pathogenesis, such as dysregulation of the hypothalamic-pituitary-adrenal glucose axis in altered plasma; insulin resistance; leptin resistance; pro-inflammatory cytokines; neuronal decrease and reduction of serotonergic neurotransmission. Clinical antidepressants are reported for resistance against obesity-comorbid depression in animal models (ISINGRINI et al. 2010).
Interestingly, selective serotonin reuptake inhibitors (SSRIs), the currently most prescribed drugs, also have an antidepressant effect by synaptic inhibition of 5-HT3 receptors (EISENSAMER et al., 2003). 5-HT3 receptor antagonists are used in the treatment of nausea and vomiting caused by the effects of chemotherapy (MAHESH et al., 2005). Some potential 5-HT3 antagonists have been reported for antidepressant effect in several preclinical studies (WOLF, 2000; ISRAILI, 2001; KURHE et al, 2014).
The mechanism of 5-HT3 receptor antagonists for the antidepressant effect is still not clearly exposed. The probable mechanism suggests allosteric modulation of the serotonergic system by synaptic antagonism of 5-HT3 receptors and thus increasing synaptic serotonin neurotransmission in various brain regions (RAJKUMAR & MAHESH, 2010).
Serotonin’s role in treating depression is well known over time. Serotonin also plays an important role in modulating HPA axis hyperactivity, leptin resistance, altered plasma glucose, insulin resistance, inflammatory cytokines, disturbance of oxidant/antioxidant balance and neurogenesis, increasing BDNF expression in hippocampus and amygdala brain regions (OWENS & NEMEROFF, 1994).
3.1 HPA axis hyperactivity
In the hypothalamus, corticotropin-releasing factor (CRF) stimulates the synthesis of adrenocorticotropic hormone (ACTH), which activates the adrenal gland and secretes glucocorticoids. Glucocorticoids exert a negative feedback effect on their receptors and inhibit the production of ACTH and FLC (FILIP, 2004). Hypofunction of the HPA axis is the result of glucocorticoid receptor (GR) resistance (KENDLER et al., 2003; HEIM et al., 2004) and the negative feedback that elevates FLC (CRF hyperdrive), (MODELL et al., 1998 ;. WOLKOWITZ, 1999; ZOBEL et al, 2001).
Stress causes a person to put on weight mainly because of an excessive secretion of the key stress hormone cortisol which is accompanied by secretion and decrease of growth hormones. Cortisol is catabolic while growth hormones are anabolic, which leads to fat accumulation, loss of muscle mass, decreased metabolic rate and increased appetite, which together have the maximum effect on gaining weight ( SHAWN, 2002).
The body secretes cortisol in order to deal with stress, under conditions of stress the cortisol level is elevated. Higher cortisol is observed in obese individuals than non-obese individuals. Cortisol is a hormone from a group of steroids commonly known as glucocorticoids. This hormone has a major impact on the body’s normal physiological functions as it increases blood sugar, blood pressure, along with suppression of immunity, thus affecting the essential element for adaptation and survival known as the “fight or flight” response. . The hormones adrenaline and cortisol are secreted by the adrenal glands with hypothalamus-mediated pituitary gland stimulation. (SALEHI et al., 2005).
Human beings have a tendency to react differently to stressors. In the first instant, in order to control the situation in case of stress norepinephrine, the hormone “fight” is predominantly released. If the stress persists and the individual feels a possible loss of control, then epinephrine, another hormone, is released. These autonomic responses can cause arrhythmias in the myocardium, as well as the release of more free fatty acids (disassembled triglycerides) into the bloodstream, prolonging stress and causing the individual to experience depressive symptoms. This in turn leads to activation of the hypothalamus in the brain which follows a cascade of hormonal pathways finally resulting in the release of excess cortisol from the adrenal cortex. Lipogenesis is elevated by the “defeat” response of the stress pathway that leads to visceral obesity, tissue breakdown, and suppresses immunity (JONES, 2001; HENRY, 1993; ELY, 1995).
Cortisol hormone plays an essential role in providing energy to the body while performing various daily physiological activities. Excess cortisol in the bloodstream causes the development of abdominal obesity, and obesity is the hallmark of various metabolic and cardiovascular diseases, such as type 2 diabetes and hyperlipidemia, respectively. (JEAN-PIERRE, 2006).
3.2 Inflammatory pathway
Data from clinical and preclinical reports have demonstrated that obesity increases adipose tissue expression and secretion of pro-inflammatory cytokines. With this concern, treatments that reduce obesity or insulin resistance have a moderating effect of reducing inflammation and associated inflammatory cytokine markers (FERRANTE, 2007).
It has been shown that IL-6 pro-inflammatory cytokines are higher in overweight children compared to normal weight controls (MCMURRAY et al., 2007) along with C-reactive protein which acts as an important biological marker of inflammation and various cardiovascular diseases in overweight people compared to overweight individuals (CINDIK et al., 2005). IL-6 and tumor necrosis factor alpha (TNF-ɑ) are reported to be higher in psychiatric patients with depressive disorder. Thus, inflammation and associated cytokines also hold the link to the pathogenesis of depression comorbid with obesity (KIM et al., 2007).
3.3 Leptin hypothesis
Leptin is a peptide known as an anti-obesity hormone. At chronic stress levels leptins are repressed. (KATZ, 1982; WILLNER, 2005). Leptin deficiency is seen in patients with depression. Several clinical studies suggest a relationship between obesity, which is characterized by increased leptin levels, and depression (FAITH et al., 2002; MCELROY et al., 2003; SIMON et al., 2006; STUNKARD et al., 2003; GIOACCHINO. et al, 1999).
Elevated leptin level in obesity is due to defects in leptin transport through altered receptor function and impaired leptin signal transduction (MUNZBERG & MYERS, 2005). Leptin plays a role in regulating the serotonin component and increases serotonin content and metabolism in the brain (CALAPAI et al., 1999; HASTINGS et al., 2002). There are also reports that leptin has a role in activating the key downstream mediator signal transducer and transcriptional activator 3 (STAT3) that regulates leptin receptor signaling on dopaminergic neurons in the ventral tegmental area (VTA), thus suggesting that possible mesolimbic dopaminergic pathway (FULTON et al, 2006;.. HOMMEL et al, 2006).
3.4 Plasma glucose adaptation or insulin resistance
The abnormal release of cortisol in the blood causes insulin resistance or altered glucose level is observed in depressed and obese populations, respectively (BROWN et al., 2004; ALMEIDA et al., 2009). In obesity, insulin resistance or altered glucose leads to lipid dysregulation (KAHN & FLIER, 2000).
Altered plasma glucose possibly reflects insulin resistance due to the association of obesity and stress that play a crucial role in obesity-comorbid depression. Insulin resistance is increased secretion of insulin from cells or loss of insulin sensitivity of the pancreas is mainly resulted due to changes in insulin receptors, insulin signaling and abnormalities in glucose transporter 4 (GLUT-4) (QUON 2001; JELLINGER, 2007).
3.5 Brain-derived neurotrophic factor (BDNF)
Brain-derived neurotrophic factor (BDNF) derived from the brain is an important regulatory protein that plays a significant role in neurogenesis and preserving the viability of newly differentiated neurons (DUMAN and MONTEGGIA, 2006). Several clinical studies have shown low levels of BDNF expression in the hippocampus, which was reversed by treatment with antidepressants (BOCCHIO-CHIAVETTA et al, 2010; BRUNONI et al, 2008).
Food intake is a complex behavior that is the result of interactions between homeostatic and hedonic regulatory mechanisms acting in the brain’s energy balance and reward centers. Changes in dietary patterns are often pervasive which can cause obesity and its associated medical complications, mainly metabolic and cardiovascular disorders and psychological distress. Recently, evidence suggests a key role for BDNF in pathological processes that lead to abnormal food intake and excessive weight gain (RIOS, 2011). Furthermore, BDNF is involved in the regulation of body weight, because its reduced expression is observed in fasting (XU et al., 2003).
3.6 Mechanisms of serotonin regulation in food intake
Serotonin is inversely related to food intake and, therefore, weight reduction agents, serotonergic analogues are well known (BREISCH et al., 1976; GARATTINI et al., 1986; GOUDIE et al., 1976). Serotonin-inducing appetite suppression is mediated through the central serotonergic pathway. The arcuate nucleus present in the hypothalamus plays an important role in the regulation of energy homeostasis (CONE, 2005; LUQUET et al., 2005). Overall, serotonin and agents that increase serotonin availability to act through 5-HT1B and 5-HT2C may play a role in the therapeutic management of obesity and its complications (ERNEST, 2007).
3.7 5-HT3 receptor antagonist of depression in comorbid obesity
The 5-HT3 receptor is the only closed ion channel of the serotonin receptor family, by conducting activation of cation flux, thus involved in membrane depolarization (HARGREAVES et al, 1994; PETERS et al., 1989). 5-HT3 receptor function depends on its location, nerve terminal or presynaptic activation of 5-HT3 receptors that leads to the release of various neurotransmitters such as serotonin, dopamine or gamma-aminobutyric acid (GABA) (VAN HOOFT et al., 2000), while activation of postsynaptic 5-HT3 receptors is involved in rapid synaptic transmission (ROERIG et al, 1997). Concerning the antidepressant effect that is achieved at very low concentrations, while higher doses are ineffective for the antidepressant effect (FAERBER et al., 2007).
Some of the currently used antidepressants have affinity for 5-HT3 receptors. Fluoxetine inhibits serotonin release, which is induced by 5-HT3 receptor agonists in the dorsal nucleus. Except for mirtazapine, the latter effect of antidepressants on 5-HT3 receptors is basically non-competitive in nature (EISENSAMER et al., 2003; KENT et al., 2000).
Serotonin and serotonergic receptor subtypes are believed to be able to mediate inhibition of food intake. An in vivo study describes that serotonin suppresses food intake which preserves the behavioral satiety sequence, ultimately indicating the natural physiological processes for sustained meal termination and post-meal satiety. Furthermore, the serotonergic drug dexfenfluramine is reported to inhibit high-diet fat consumption in rodents. Human studies confined to suppression of highly palatable high-fat food intake and possible fat prevention after administration of sumatriptan and dexfenfluramine (BLUNDELL et al., 1998).
A serotonin release or uptake inhibitor, fenfluramine is reported to inhibit food intake in both animals (DUHAULT et al., 1976) and humans (SILVERSTONE et al., 1986). Serotonin acts mainly on the medial hypothalamus. The paraventricular and ventromedial nuclei are involved in controlling energy balance, while the suprachiasmatic nucleus regulates circadian feeding patterns (LEIBOWITZ et al, 1990).
Thus, from the above data and literature, it is quite clear that 5-HT2C receptor agonists or the agent that increases the availability of serotonin to act through 5-HT2C receptors can be useful for the treatment of obesity and diabetes. Thus, allosteric modulation of the serotonergic system that increases synaptic serotonin neurotransmission in various brain regions and through other serotonergic receptors could play an important role in the treatment of depression associated with obesity (LAM et al., 2008).
3.8 Antidepressants in magistral formulations
In magistral formulations, antidepressant substances are commonly indicated in associations to induce anorexia, aiming at weight loss. The use of fluoxetine in weight loss formulas was even condemned by the US Food and Drug Administration (FDA) (ROSSI, BARRACO & DONDA, 2004).
In the treatment of anorexia nervosa, for example, it is very common to incorporate in their formulations the use of antipsychotic drugs such as pimozide, sulpiride and other agents such as cyproheptadine, lithium, tetrahydrocannabinol, clonidine, natrexone, growth hormone, zinc and cisapride and tricyclic antidepressants. The use of antipsychotics is justified by the manifestation of body distortion in the patient, which can be considered a form of psychosis, the doses used, especially of antidepressants, are often low (GIORDANI, 2011).
The use of antidepressants should be considered mainly in cases where the individual has depression, obsessive-compulsive symptoms or anxiety. Selective serotonin reuptake inhibitors are the most researched, as they have been showing greater safety in the incorporation of the magistral formulation for weight control. Studies present evidence that suggest the beneficial effects of using fluoxetine during the maintenance phase, after weight recovery, which may reduce the risk of relapses, even though there are still no studies focused on controlled individuals proving its effectiveness, some case reports suggest a relative benefit in the use of fluoxetine. psychotropic drugs in small doses, mainly in people who are anxious, agitated and with severe obsessive-compulsive traits (HOEK, 1995).
The use of some drugs that have been shown to be useful in the treatment is still quite controversial (such as topiramate and sibutramine), but further studies are still needed to define their real efficacy, safety in treatment and in formulations (BACALCTHUK, 1999; BORGES & JORGE, 2000).
However, the use of fluoxetine in weight loss formulas has been condemned by the US Food and Drug Administration (FDA, 2006).
“Two Brazilian diet pills, the ‘Emagrece Sim Dietary Supplement’ (also known as ‘Brazilian Diet Pill’) and the ‘Herbathin Dietary’ Supplement’, manufactured by Laboratorios Fitoterápicos (also spelled Fytoterapicos) and Phytotherm Sim, contain active drugs, including controlled substances, which may cause serious adverse reactions or patient harm, and furthermore, both products have not been approved by the FDA.”
The FDA states that these products contain several substances, among them, (FDA, 2006).
“‘fluoxetine’, which features numerous case reports that have interactions with other drugs and adverse effects, including suicidal ideation and behavior in children, anxiety, insomnia and abdominal bleeding”
According to Cabrera (2006) antidepressants are effective in reducing the symptoms of bulimia and treating associated psychiatric disorders, even if people demonstrate resistance to their use. Some antidepressants such as serotonin inhibitors help to reduce compulsion and vomiting, and are relatively safe over a period of 6 months to 1 year.
In a report by Salzano & Cordás (2004), they are in agreement with the study above, which present the use of antidepressants in focus on tricyclics and selective serotonin breakdown inhibitors, which help in bulimia by reducing these episodes of vomiting acting on anxiety. Topiramate promotes a decrease in appetite and weight loss in some patients, which provides some favorable and controversial studies in this same segment.
Available statistics demonstrate that the number of deaths resulting from the use of prohibited psychoactive substances is compared with the number of deaths caused by licit drugs, mainly antidepressants and medication for slimming drugs (OLMO, 1992).
CNS drug associations are alarming, given that they both increase the risks of abuse and chemical dependence, as well as imply a series of aspects to consider in relation to the indications, adverse effects and, fundamentally, the pharmacological interactions of anorectic drugs, which, in some cases, they can even cause irreversible and fatal complications (BEHAR, 2002). Benzodiazepines are included in these formulations with the aim of promoting a reduction in the state of excitability (“nervousness”, fine tremors of the extremities, insomnia, caused by catecholaminergics), and these drugs should only be used in patients with well-defined clinical anxiety. In addition, three to four months of continuous use in the usual dosages can already promote dependence and abstinence syndrome (NAPPO et al., 1994). When associated with catecholaminergic, there is the possibility of changes in the bioavailability of the drug, since it is metabolized by cytochrome P-450 (BEHAR, 2002).
4 Conclusion
With this bibliographic review it is possible to conclude:
Dysfunction of the HPA axis is primarily involved in depression associated with obesity;
Pro-inflammatory cytokines can be considered as a pathogenic factor in common with obesity-associated depression;
Leptin is one of the main contributing factors in the pathogenesis of depression comorbid with obesity;
BDNF expressions are reduced when experiencing depression associated with obesity;
Serotonin assists in appetite regulation and depression. 5-HT3 are receptor antagonists acting by modulating the serotonergic system by increasing serotonin neurotransmission in various regions of the brain and have an antidepressant effect by reducing appetite;
Selective serotonin reuptake inhibitors are the most used in magistral formulations to help control weight, prescribed mainly for individuals who have anxiety or depression;
In magistral formulations, antidepressants are used in small doses to maintain the patient’s clinical condition;
The prescription of antidepressants in slimming formulas is still much discussed, resulting in numerous questions and its true application in weight loss.
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1 Centro Universitário Serra dos Órgãos (UNIFESO), Teresópolis, Rio de Janeiro, Brasil.
2 Centro Universitário de Brasilia (UniCEUB), Brasília, Destrito Federal, Brasil.
3 Universidade Federal de Mato Grosso (UFMT), Cuiabá, Mato Grosso, Brasil.
4 Universidade Alto Vale do Rio do Peixe (UNIARP), Caçador, Santa Catarina, Brasil.
5 Centro Universitário UniFTC, Itabuna, Bahia, Brasil
6 Centro de Ensino Unificado de Brasília (CEUB), Asa Norte, Brasília, Brasil
7 Universidade Evangélica de Goiás (UniEVANGELICA), Anápolis, Goiás, Brasil.
8 Universidade Ibirapuera (UNIB), Chácara Flora, São Paulo, Brasil.
9 Universidade Federal do Cariri, Barbalha, Ceará, Brasil.
10 Centro de Longevidade Irineu Mazutti, Sumaré, São Paulo