Antipsychotics (AP) are drugs commonly used in clinical practice in the treatment of psychosis and other serious mental illnesses in both adults and adolescents, because they have proven to be effective in controlling a wide spectrum of symptoms but they are often associated with the increase of 'appetite and weight gain”, with an increased risk of developing diabetes and other important metabolic diseases.

Since the introduction in the late 60s of last century, the first antipsychotics (first generation antipsychotic FGA), it was shown that these drugs could cause weight gain unquestionable because the event was, to some extent, obscured by the more frequent and impressive events related to extrapyramidal effects (EPS). Only in recent decades, with the prevalent use of atypical antipsychotics (second generation antipsychotic SGA), which have significantly reduced the incidence of EPS, weight gain and metabolic implications have led to greater attention by clinicians.

Overweight and obesity are beyond treatment, often in patients with schizophrenia or bipolar. It is estimated that patients with psychotic or other major mental illness, made a double incidence of obesity than the general population [1], with a ratio of up to three times more intra-abdominal fat compared to age, gender and lifestyles [2]. In addition, patients with schizophrenia have an increased risk for the onset of complications related to obesity, not only for possible genetic link between the two diseases, but also for the presence, often, altered lifestyles is not correct, smoking, alcohol abuse, sedentary lifestyle, etc..) [3]. Among the metabolic alterations potentially induced by the AP weight gain is usually but not always, the first manifestation and can lead to obesity in short time, which often is associated with dyslipidemia, glucose intolerance and type 2 diabetes later. The cardiovascular complications associated with these changes help to increase the incidence of death from cardiovascular disease and reducing life expectancy among patients with severe mental illness. Some recent epidemiological work found that schizophrenic patients have a mortality risk of up to 2.5 times higher than the general population, matched by age and sex [4,5], with a 'life expectancy to about 20% in less [6]. Cardiovascular diseases are responsible for more than 50% of mortality in the population with schizophrenia [7].

To date, the possible metabolic changes induced by various AP drugs and their important consequences, are among the major concerns of clinicians in the practice of psychopharmacological therapy.

Overweight and obesity are clinical conditions that involve an increase in body fat and are currently classified by assessing body mass index (body mass index, BMI). The BMI is a factor that involves not only the variable weight but intersects with variable height. In this way you get a big advantage, because with only one value, you can express two different variables. The BMI is calculated by dividing weight in kilograms with the square of height in meters (kg / m²). BMI between 18.5 and 24.9 are indicative of normal, between 25 and 29.9 are indicative of overweight and over 30 shows obesity [4].

The condition of overweight, especially obesity, significantly reduces life expectancy because it is associated with major diseases, both physical and psychological. Obesity increases the risk of developing diabetes, arthritis, respiratory diseases, cancer, metabolic syndrome, stroke and cardiovascular disease [5]. Obesity, especially the increase in visceral fat in the abdomen, was significantly associated with insulin resistance that causes abnormal glucose metabolism, increased triglycerides, increased low-density lipoprotein (LDL), hypertension, abnormal coagulation which, together, induce a marked increase in coronary risk [6, 7]. Also, many evidences of the literature, shows that obesity is associated with depression (in the U.S. among obese women, the incidence of depression is considered to be around 35%), decreased self-esteem, guilt, shame and increase the social stigma which, of course, reduces the perceived quality of life [8, 9] .

The use of antipsychotic drugs, including SGA, can commonly cause weight gain, several studies have evaluated the 'incidence between 50 and 80% of patients [10], with a weight gain estimated at approximately 10% [10]. As the AP class of drugs is quite heterogeneous, the effects on weight gain is quite variable between different agents [11].

The Consensus Development Conference on antipsychotic Drugs and Obesity and Diabetes, comparing various evidences of the literature on the metabolic effects of the AP, found that clozapine and olanzapine are more closely linked to weight gain, followed by risperidone and quetiapine, and ziprasidone and aripiprazole may induce little or no weight gain [12].

A recent meta-analysis by Steven Leucht et al. [13] compared haloperidol, a FGA, with several SGA and found that clozapine, olanzapine and sertindole induced a greater increase in weight over 3 kg haloperidol.

The National Institute of Mental Health, in a large observational study, randomized controlled trial (CATIE), lasting 18 months, showed that patients treated with olanzapine had taken an average of 4.3 kg, those treated with risperidone 0, 36 kg, 0.50 kg while those patients treated with quetiapine and ziprasidone perphenazine had lost respectively 0.91 and 0.73 kg [14].

A significant factor in increasing susceptibility to weight gain induced by AP was found to be the onset of the disease. The European First Episode Schizophrenia Trial (EUFEST) [15], a study of schizophrenic patients over a year on the first episode of illness, showed a marked weight gain during treatment with AP. Olanzapine induced an increase of 13.9 kg, 10.5 kg of quetiapine, ziprasidone of 4.8 kg while the haloperidol of 7.3 kg.

Significant weight gain was shown in another trial, randomized, double-blind, lasting about one year, first-episode patients treated with some of the most widely used EMS, the comparator of Atypical in First Episode of Psychosis ( CAFE ') [16]. Weight gain was assessed through a valid clinical indicator: weight gain of more than 7% from baseline. With almost 80% of olanzapine-treated patients has exceeded 7% of initial weight compared with 58% of the risperidone group and 50% of the quetiapine group. Even a recent study [17] showed a marked weight gain in patients with a mean age of 27 years, drug-naive first-episode psychosis was treated with AP. On 128 patients treated with haloperidol, olanzapine and risperidone in 12 weeks of treatment, there was an average increase of 5.7 kg (3.8 kg with haloperidol, olanzapine 7.5 kg and 5.6 kg with risperidone).

The mechanism by which AP induces weight gain is complex and multi-determined, or are deemed to be necessary social conditions that contribute together, rather than a single triggering event.

Basically, the AP determined, through various mechanisms and then try to analyze in detail, increased appetite, and then the food-intake and a reduction, albeit modest, energy consumption [18].

Weight gain induced by AP could also show considerable individual variability, even in patients taking the same drug. Of course, the different lifestyles of individual patients is an important but not decisive by itself, several other conditions may become predisposing to weight gain.

Various clinical parameters can be used as possible predictors of weight gain. Among these may include the dosage and duration of treatment, the period of illness, age, sex, race, smoking, environmental factors, genetic factors and the deviation from normal (BMI) and premorbid before the beginning of treatment [19]. In fact, subjects with lower BMI tend to gain weight to a greater extent than patients who are already overweight or obese before treatment [20]. In addition, younger patients, especially women, the first psychotic episode, seems particularly vulnerable to increased AP-induced weight gain [18-20] The use of other drugs (some mood stabilizers, antidepressants and benzodiazepine drugs among the general or common use of drugs such as steroids, estrogen progestin, antihistamines, etc.) in association with the AP was also associated with greater weight gain than the monotherapy [21]. Of course, the interactions between different molecules, doses used, the severity of underlying disease and comorbidities make complex issues and analysis of observed data.

Drug interactions of AP, are the levels of the central nervous system (hypothalamus and brain stem in particular) that in the suburbs, with some neurotransmitters, neuropeptides and hormones (eg insulin, ghrelin, leptin and other adipokines), determine an imbalance of the neuroendocrine network control energy homeostasis and body weight.

The clinical effect of AP is manifested by modulating the action of neurotransmitters and interacting with their membrane receptors. Binding to dopamine D2 receptors (both antagonism of partial agonism) is at the time is essential for the effectiveness of antipsychotic and it is the only mechanism common to all AP approved by various international regulatory bodies. However, as we know, the AP is a very heterogeneous class of drugs with multiple actions on different receptors, such as serotonin, muscarinic, histaminergic and noradrenergic and with different degrees of affinity.

The receptors are those most associated with increased weight serotonin 2C (5-HT2C), histamine 1 (H1) and H3 autoreceptors and also the D2 dopamine receptor, although little has been studied from this point of view. In fact, the blockade of D2 by the AP can alter energy metabolism, either by altering the signaling that reduce the physical activity [22]. The antagonism by the AP on all of these receptors at central level, causes a marked increase in food-intake through an increase in appetite and reduced ability to perceive the feeling of satiety [11,12].

Studies in animal models, mice knocked out for 5HT2C receptor gene, have provided interesting results because they simulated the effect of pharmacological blockade of these receptors resulting in these animals a state of hyperphagia, which further results in obesity and chronic hyperinsulinemia [23].

Furthermore, the antagonistic action of AP on H1 and H3 receptors are present on the arcuate and paraventricular nuclei of the hypothalamus. The mediated activation of second messenger adenosine monophosphate kinase (AMPK), not only increases the appetite by stimulating the streets orexigene through the 'activation of age-related protein (AgRP), but also by inhibiting the ability of the anorexigenic leptin in the hypothalamus [12, 13, 20]. To control the complex mechanism, other receptors appear to be involved, albeit to a small extent, such as alpha-adrenergic receptor 1α [21] and sterol regulatory element binding protein (SREBP).

The SREBP transcription factors are important regulators for cell biosynthesis of cholesterol and triglycerides. Both the SGA and FGA seem to activate the system of SREBP-controlled lipogenesis in human hepatocytes [13, 24]. Although muscarinic receptors 3 (M3) are involved in increasing weight gain induced by AP, albeit indirectly. In fact, the blockade of M3 receptors in the pancreatic beta cell, mostly due to the SGA, induces alterations in glucose metabolism due to reduction in insulin secretion and increased insulin resistance [25,26]. The different receptor profiles of the various AP account for the different skills that individuals possess AP drugs induce weight gain. Both clozapine to olanzapine, more drugs involved in increasing the weight, are characterized by a higher affinity for H1 receptors and 5-HT2C. Risperidone, which has a lower affinity for H1 receptors and 5-HT2C, is less involved in inducing weight gain. Ziprasidone, conversely, is a potent 5-HT1A receptor agonist and 5-HT2C receptor antagonist and a modest effect on weight may be interpreted through the inhibition at the synaptic re-uptake of serotonin and norepinephrine [14]. Aripiprazole, however, has a peculiar action of D2 receptor partial agonist and 5-HT1A. The essential neutrality of action on the weight is attributable to the modest affinity for H1 receptors and 5-HT2C [15].

Many studies have shown that the AP, in particular SGA, more strongly implicated in increasing weight, can cause alterations of the neuroendocrine network that controls appetite, food-intake and the perception of satiety. The data in the literature, at the time, show a predominant involvement of insulin, leptin, adiponectin, orexin, ghrelin and prolactin.

It is of common evidence in clinical practice, which in some patients are more susceptible than others to gain weight during treatment with AP. In some patients, in fact, weight gain may begin after a few rounds of initiation of therapy and is irreversible, even after reducing the dose or switching to other drugs. This finding underlines the hypothesis of a genetic susceptibility factor that favors the clinical expression of AP-induced weight gain. Several studies have suggested that a single nucleotide polymorphism (SNP single nucleotide polymorphism) of 5-HT2C receptor (-759 T / C gene HTR2C) is associated with increased susceptibility to weight gain and metabolic syndrome induced by AP [33]. A meta-analysis of eight studies showed that patients treated with AP, carrying the C receptor 5HT2C had more than twice a risk of weight gain significantly (≥ 7% of initial weight) than carriers of allele T [46]). Some studies ([47,48] on a large cohort of the population, have linked obesity to carry the C also present in the general population and therefore the use of AP, in carriers of this polymorphism, can speed up or increase the ' weight gain, which tends to have favor this change in gene expression. It has also been suggested that the polymorphism of 5-HT2C receptor induces a reduction of the anorectic effect of leptin in the hypothalamus [34].

In addition, other recent works have shown that polymorphisms transporter serotonin (SERT), such as the presence of the short allele, are associated with weight gain induced by olanzapine which is significantly higher compared with control patients [35]. In addition to these there are several candidate genes to increase susceptibility to the increase in metabolic diseases favored by treatment with AP and the current genomic studies of the drug have estimated them around 300 genes [36].

The results of linkage studies and genome-wide affect specific genes, such as the promelanin concentrating hormone (PMCH), the polycystic kidney and hepatic disease 1 (PKHD1), the peptidylglycine α-amidating monooxygenase (PAM) and endocannabinoid receptors. Others include the α2a adrenergic receptor gene (ADRα2a), for leptin, ghrelin, for TNF to adiponectin, for the G protein and the D2 receptor [13, 36-38]. In a recent study was found a significant relationship between the polymorphism (DRD2-141C Ins / Del) for the section that affects the gene transcription of the dopamine D2 receptor and weight gain induced by AP [49].

Patients treated with AP (randomized between risperidone and olanzapine), carriers of the DRD2 Del, i.e. without nucleotide in that position, compared with patients homozygous instead ofIns / Ins, presented a weight gain of about 6 pounds at six weeks and about 15 pounds at the sixteenth week of observation.

In addition, a single nucleotide polymorphism of the adrenergic receptor gene (ADRA1A), is implicated in increased vulnerability increased AP-induced weight gain, particularly in young women (40). Some gene variants appear to be involved in metabolic drug-induced AP, as MEIS2 a polymorphism that increases abdominal circumference, which is one of the most significant indicators for intra-abdominal adiposity [50]. Conversely, a polymorphism of the cannabinoid receptor (CNR1 rs806378) was associated with a particular resistance to weight gain induced by AP. Patients carrying this allele gained about 2.2 kg less during treatment with clozapine or olanzapine compared to patients who are non-carriers [39].

The metabolic syndrome (MS) is defined as a constellation of interrelated risk factors, which confers an increased risk for the development of stable hypertension, diabetes mellitus type 2 and cardiovascular diseases. The criteria for the MS diagnosis include a number of factors such as high blood glucose, atherogenic dyslipidemia, characterized by substantial levels of triglycerides and low HDL cholesterol levels which tends upward of systolic and diastolic blood pressure and abdominal obesity [51]. The increase of fat deposited in the abdomen is an important risk factor for obesity-related diseases. The measurement of waist circumference (waist circunference: WC), with values ​​greater than 102 cm and 88 cm in males and females, significantly correlated with increased cardiovascular risk [52-54]. Individuals with MS also have clinical and biochemical changes, as with pro-thrombotic and pro-inflammatory [46].

The criteria, defined and internationally accepted standards for the diagnosis of metabolic syndrome are summarized in Table 1.

The values ​​most widely used are those proposed by the Adult Treatment Panel III of National Cholesterol Education Program (ATP - NCEP III) in 2001 and revised in 2003 [43].

It is important to stress that it is not necessary that an order established a state of frank diabetes or obesity or a major dyslipidemia or hypertension net for the diagnosis of MS, but it is sufficient, as shown in the table, the presence, at the upper limits of normality, at least three of these clinical indices.

It is believed that three pathogenic mechanisms have a substantial role in determining the development of MS:

1. insulin resistance (or low insulin sensitivity) or the medical condition in which insulin exerts a biological effect of lower than expected;
2. the accumulated fat, especially visceral, with its functional disorder of adipose tissue, with a change in the production of hormones released by adipocytes, called adipokines (leptin, adiponectin, TNF, IL1, IL 6, apolipoprotein E, angiotensinogen , PAI-1, etc..), which strongly influence the glucose and lipid metabolism;
3. the production of a number of factors from the liver, vascular and immunological [44].

The increase in free fatty acids (FFA) in the circulation, secondary to an alteration of lipid metabolism plays an important role in the pathogenesis of insulin resistance through a specific blocking action on the signal transduction of insulin. In addition, increased blood concentrations of FFA, promotes oxidative stress, inflammatory status and an alteration of vascular reactivity that further contribute to insulin resistance [55].

MS is a disease quite common in the general population and the prevalence varies according to BMI, age, gender and ethnicity. Population studies [56], based on the Third National Health and Nutrition Examination Survey (NHANES III), the United States has assessed its impact on the whole about 22% of the general population and over 60% in the obese population (BMI> 30). In Europe and in Italy the incidence of MS is slightly lower. MS is considered to be the most common cardiovascular risk factor in the Western world and in many developing countries, in fact, it is characterized by the simultaneous presence of several risk factors that directly contribute to the development of 'atherothrombosis and is associated with twice the risk for cardiovascular events and up to 5 times higher for developing type 2 diabetes. Moreover, this risk increases progressively and linear in relation to the number of elements that characterize the SM present in the individual patient [7, 45, 57]). The association between severe mental illness such as schizophrenia and bipolar disorder, with the onset of MS is largely known for several years, but some recent reviews have clearly shown , this association [54, 58-60].

De Hert et al. [47], in a review of 38 studies published between 2003 and 2008 showed that the incidence of MS is two to three times higher in schizophrenic patients than the general population.

Meyer and Stahl [48], in a review of 11 studies reported not only a significant presence of MS in patients with chronic schizophrenia but also that the MS has an earlier onset in patients with schizophrenia than the general population.

In addition, in the study by CATIE [49], about a third of the patients had observed the criteria for MS at baseline. In a recent trial [50] schizophrenic patients followed up between 2000 and 2006, treated with SGA, were compared with schizophrenic patients followed between 1984 and 1995, treated with FGA, and it was found that the incidence of MS SGA, 27.8% vs 9.8% was significantly higher.

Finally, several studies [51, 52] have shown that children and adolescents treated with AP, are at increased risk of developing MS and weight gain, compared to adult patients who are taking the same drugs. Of course the use of AP drugs, not only causes weight gain, visceral adiposity but also promotes the incidence of MS in these patients. Recently [30] significantly increased adiposity, both subcutaneous and intra-abdominal, as assessed by MRI in a group of drug-naive schizophrenic patients, followed for 10 weeks treatment with AP was reported.

However, in approximately 25% of patients treated with AP, without weight gain or marked visceral adiposity, MS was present, suggesting a direct link between the metabolic action of drugs AP and the presence of SM [53].

Many psychoactive drugs are able to induce weight gain and are capable of inducing significant metabolic diseases. APs are certainly in this respect, the drugs most involved and most studied.

Overall, the data collected from the international literature, especially in the last decade, suggest that metabolic abnormalities in patients with severe mental illness and thus increase the risk of developing cardiovascular disease associated with it, which is linked to a number of concomitant risk factors, such as: an individual's genetic vulnerability, the very presence of underlying psychiatric illness etc., to assume genetic links; incorrect lifestyles and not the least, the use of drugs such as AP. Despite much research, carried on acute shortage of patients, the mechanisms underlying these events are not yet entirely clear, even to the obvious complexity of these networks, linked to the substance for the survival of the species, such as control of 'feeding and energy balance. The key mechanisms appear to be related to alterations in the regulation of the perception of hunger / satiety and energy homeostasis, and involve both receptors in the hypothalamus, 2c 5HTC for serotonin, histamine H1, for endocannabinoids and dopamine transmission and alpha-adrenergic, and hormones, neuropeptides and their receptors that control airway and peripheral orexigene and anorexigenic. Moreover, the presence of several polymorphisms and some genes that control the synthesis of certain receptors or transporter, is associated with increased susceptibility to weight gain and metabolic syndrome.

Many studies, mostly of drug epidemiology and genomic medicine will be needed in the near future to differentiate even more specifically between the drugs ability to induce metabolic changes and especially to evaluate the influence on the individual patient in the treatment of certain confounding variables, such as family history and personal experience for cardiovascular and metabolic diseases, lifestyle, type and stage of basic psychiatric illness, the use of previous treatments, comorbid somatic and mental el 'presenceof several treatments.

In conclusion, all the AP, with a prevalence of SGA on FGA, can increase metabolism and thus the cardiovascular risk ,and therefore it is necessary that clinicians should always take into account these possible adverse effects of treatment. Therefore, to maintain physical health it is also necessary to monitor metabolic parameters (Table 2) in all patients treated with the AP, even in the absence of marked overweight or obesity; encourage and support patients adopt healthy life styles and a healthier eating, or use psychoedu-cational interventions, including medication, if necessary, to minimize the metabolic events related to the use of AP. Threfore, it is recommanded to select the drug when the patient's clinical condition permits, the AP with the least impact on drug metabolism and, finally, consider the physical health of patients with mental illness as an integral part of patient care, actively collaborating with other health care facilities, such as primary care and specialist.