Mechanisms of Increased Appetite and Weight Gain Induced by Psychotropic Medications

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1 12 Journal of Advanced Clinical Pharmacology, 2014, 1, Mechanisms of Increased Appetite and Weight Gain Induced by Psychotropic Medications Adam Wysoki ski* and Iwona K oszewska Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Poland Abstract: Weight gain is a common and serious consequence of treatment with psychotropic medications. Medications may affect neuronal circuits that regulate appetite (direct orexigenic effect), as well as other systems that regulate energy homeostasis. In this paper we will detail four groups of neurobiological mechanisms involved in the direct orexigenic effect of antipsychotics, antidepressants and mood stabilizers: (1) neurotransmitters, (2) neuropeptides (leptin, ghrelin and neuropeptide Y, in particular), (3) neuroendocrine system (insulin and prolactin, in particular) and (4) other mechanisms (resting metabolism, inflammatory cytokines). Moreover, all these interactions may be modified by genetic polymorphisms, which will also be summarized. Keywords: Appetite, weight gain, antipsychotics, antidepressants, mood stabilizers. INTRODUCTION Most psychiatric medications can cause some weight gain. Weight gain of 7% or more is considered clinically significant according to American Diabetes Association and American Psychiatric Association definition for studies of psychotropic drugs [1]. Some clinicians use the body mass index (BMI) to monitor patients weight, but since it poorly reflects changes in body fat, other measures are developed and used, such as fat mass index (FMI) [2]. Weight gain is a common and serious consequence of treatment with psychotropic medications [3]; this refers to antipsychotics [4], antidepressants [5] and mood stabilizers [6]. Treatment-induced weight gain not only reduces quality of life and have important effect on somatic commorbidities, but also has been linked with treatment non-adherence [7], which is particularly common in patients with schizophrenia (it is estimated that in this group rate of non-adherence ranges from 40 to almost 80%) [8]. Weight gain plays a key role in the development of insulin resistance and results in metabolic syndrome (MetS). The prevalence of MetS in adults taking antipsychotics may be more than two times higher comparing to general population [9]. This problem also affects patients with uni- and bipolar affective disorders [10]. Somatic consequences of treatment-induced weight gain may significantly reduce lifespan of people with serious mental illness [11]. Weight gain induced by psychotropic medication is a multifactorial phenomenon. Medications may affect *Address correspondence to this author at the Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz Czechoslowacka 8/10, Lodz, Poland; Tel: ; Fax: ; adam.wysokinski@gmail.com neuronal circuits that regulate appetite (direct orexigenic effect), as well as other systems that regulate energy homeostasis. In this paper we will detail four groups of neurobiological mechanisms involved in the direct orexigenic effect of psychotropic medications: (1) neurotransmitters, (2) neuropeptides (leptin, ghrelin and neuropeptide Y, in particular), (3) neuroendocrine system (insulin and prolactin, in particular) and (4) other mechanisms (resting metabolism, inflammatory cytokines). Moreover, all these may be modified by genetic polymorphisms, which will also be summarized. It should be kept in mind that increased appetite may also be a result of reduced severity of psychopathological symptoms, for example depression or psychosis (e.g. delusions of being poisoned) [12]. Changes in diet and physical activity during in-hospital treatment may also result in weight gain or metabolic abnormalities, e.g. lipids or glucose profile [13]. BASIC MECHANISMS OF APPETITE REGULATION Appetite is the desire to eat food, felt as hunger. In contrast, satiety is the absence of hunger; it is the sensation of feeling full. Appetite is regulated by numerous integrated interactions between gastrointestinal tract, adipose tissue and central nervous system (CNS). These interactions are affected by mechanisms of behavioral, sensitive, autonomic and endocrine nature. Appetite (and thus body weight) regulating mechanisms are divided into two groups: (1) satiety signals: short-term regulatory mechanisms that determine hunger and satiety before and after a meal, respectively and (2) adiposity signals: long-term mechanisms that regulate energy storage in adipose tissue. Short-term regulatory mechanisms are functionally linked with the gastrointestinal tract and E-ISSN: / Pharma Publishers

2 Increased Appetite and Weight Gain Induced by Psychotropic Medications Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No Table 1: Appetite Modulators, their Receptors and Effect on Target Regulatory Structures Modulator Receptor Effect on appetite regulating systems POMC/CART neurons NPY/AgRP neurons PVN VMN LHA brain stem Anorexigenic system Insulin INSR (+) (-) Leptin LEPR (+) (-) (+) (+) (-) (+) Adiponectin ADIPOR1/2 (+) (-) -MSH MC4R (+) (-) CART (+) (+) TNF- TNF-R1 IL-1 IL1R (CD121) (-) (+) IL-6 IL6R (CD126) (-) (+) OXM GLP-1R (+) (+) PP Y4/5R (+) GLP-1 GLP-1R (+) (-) (+) CCK CCKAR CCKBR (+) PYY Y2R (-) (+) IAPP GPCR+RAMP1-3 (-) (+) Orexigenic system NPY Y1-5R (-) (-) (+) AgRP MC3/4R (-) (-) OXA, OXB OXR1/2 (+) (-) Ghrelin GHSR (-) (+) (+)/(-) Galanin GALR1 (+) (+) Glucocorticoids GR (+) Endogenous opioids DOP-R KOP-R MOP-R (-) (+) (+) Endogenous cannabinoids CB1R (-) (+) (+) (+) - activation; (-) - inhibition; POMC - pro-opiomelanocortin; CART - cocaine and amphetamine-regulated transcript; NPY - neuropeptide Y; AgRP - agouti-related protein; PVN - paraventricular nucleus; VMN - ventromedial nucleus; LHA - lateral hypothalamic area; -MSH - -melanocyte-stimulating hormone; TNF- - tumor necrosis factors- ; IL-1 - interleukin 1 ; IL-6 - interleukin 6; OXM - oxyntomodulin; PP - pancreatic polypeptide; GLP-1 - glucagon-like peptide-1; CCK - cholecystokinin; PYY - peptide YY; IAPP - amylin; OXA - orexin A; OXB - orexin B. form the gut-brain axis. Long-term mechanisms originate from adipose tissue [14]. A summary of information on appetite-regulating substances, their receptors and effect on target structures is shown in Table 1. Figure 1 shows the central system of appetite regulation. The major drawback of this scheme is that is does not illustrate dynamic plasticity of connections between individual areas. The whole system dynamically responds to changes in internal and external environment and is not - as similar schemes would suggest - a static network of neuronal and hormonal connections. Hypothalamic nuclei (and arcuate nucleus (ARC) in particular) play the key role in appetite regulation. The primary role of ARC results from its anatomical properties - it is located at the base of the brain and is not fully insulated from the circulation by the bloodbrain barrier. Therefore, nutrients and peripheral regulatory factors have a direct access to this nucleus. In ARC there are several types of neurons that synthesize pro-opiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY) and agouti-related protein (AgRP). These groups of neurons form a primary regulator of hunger

3 14 Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No. 1 Wysoki ski and K oszewska Figure 1: Central system regulating appetite and energy homeostasis. HYP - hypothalamus; ARC - arcuate nucleus; NTS - nucleus of the solitary tract; AP - area postrema; DMNV - dorsal motor nucleus of the vagus; PFC - prefrontal cortex; PVN - paraventricular nucleus; LHA - lateral hypothalamic area; VMN - ventromedial nucleus; POMC - pro-opiomelanocortin; CART - cocaine and amphetamine-regulated transcript; NPY - neuropeptide Y; AgRP - agouti-related protein; -MSH - -melanocyte-stimulating hormone; MC4R - MSH receptor subtype 4; Y1R - NPY receptor subtype 1; GABA - gamma-aminobutyric acid; DA - dopamine; TRH - thyrotropin-releasing hormone; CRH - corticotropin-releasing hormone; MCH - melanin-concentrating hormone; OXA - orexin A; OXB - orexin B; LEPR - leptin receptor; GHSR - ghrelin receptor. and satiety [15]. The following structures are connected via these neurons: paraventricular nucleus (PVN), lateral hypothalamic area (LHA) and ventromedial nucleus (VMN). These structures form a secondary regulator and have a direct effect on mechanisms that regulate energy homeostasis. LHA, the hunger center, activates hormonal and behavioral mechanisms associated with food intake and energy storage. PVN and VMN act as satiety center, inhibit appetite and activate catabolic processes. The actions of both groups of arcuate nucleus neurons are opposite - anorexigenic POMC/CART neurons activates PVN and inhibits LHA via -melanocyte-stimulating hormone ( - MSH) (a cleavage product of POMC). This way they activate satiety center and inhibit hunger center. In both centers -MSH acts via MC4R receptors. Orexigenic NPY/AgRP neurons activate LHA and inhibit PVN and thus activate hunger center. PVN is inhibited by agoutirelated protein (AgRP), which has antagonistic properties on -MSH, while neuropeptide Y (NPY) activates LHA neurons via Y1R receptors. PVN neurons that are activated by -MSH release thyrotropin-releasing hormone (TRH) and corticotropinreleasing hormone (CRH), which reduce appetite and activate catabolic processes. LHA neurons, activated by NPY, release melanin-concentrating hormone (MCH) and orexins A and B (OXA and OXB), which induce appetite and activate anabolic reactions [16]. VMN includes neurons that are sensitive to bloodglucose levels. In response to normal blood glucose levels these neurons send signals to PVN and inhibit further intake of glucose with food [17]. The majority of these neurons have NPY receptors and are inhibited by this neuropeptide. Modulation of ARC neurons results not only from activation and inhibition via particular

4 Increased Appetite and Weight Gain Induced by Psychotropic Medications Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No neuromediators, but also via synaptic plasticity, which was demonstrated for NPY/AgRP neurons and POMC neurons [18]. Activity of ARC is regulated by several hormonal factors. These hormones are secreted in the gastrointestinal tract and by adipose tissue. The former forms a short-acting system, which regulates initiation and termination of food intake. This system includes anorexigenic hormones: pancreatic polypeptide (PP), cholecystokinin (CCK); glucagon-like peptide-1 (GLP- 1), oxyntomodulin (OXM), peptide YY (PYY) and one orexigenic substance: ghrelin [19]. There is also a longacting system, which regulates the amount of adipose tissue. This system includes two hormones: leptin and insulin and cytokines: interleukin 1 and 6 (IL-1, IL-6), tumor necrosis factor (TNF- ) and others [20]. Neuronal signals originating from mechanoreceptors and chemoreceptors of the gastrointestinal tract are transmitted via the vagus nerve and sympathetic system to the nucleus of solitary tract (NTS) in the brain stem. These signals are converged in NTS and then transmitted to PVN, where they modulate activity of PVN neurons. Signals from hunger and satiety centers modulate NTS neurons and thus form large feedback loops [21]. In the brain stem there are also other structures involved in appetite regulation - area postrema (AP) and dorsal motor nucleus of the vagus (DMNV). MECHANISMS OF INCREASED APPETITE INDUCED BY PSYCHOTROPIC MEDICATIONS Role of Neurotransmitters Numerous receptors for neurotransmitters required for clinical activity of psychotropic medications are also responsible for their disadvantageous effect on body weight. This is particularly true for histamine H1 and serotonin 5-HT2C receptors antagonism. These receptors are responsible for weight gain induced by e.g. clozapine, quetiapine, olanzapine, risperidone and antidepressants. Serotonin Receptors De Vry and Schreiber published a review of studies of serotonin receptors 1A, 1B, 2B and 2C agonists and showed important role of these receptors in maintaining energy homeostasis (both at the level of appetite regulation, food intake and eating behaviors) [22]. Results of these studies are similar to the relationship between observed (in humans) affinity of individual psychotropic medications to subtypes of serotonin receptors and potential of these medications to induce weight-gain. (a) 5-HT1A 5-HT1A receptor is directly involved in the regulation of appetite, probably via modulation of noradrenergic and dopaminergic neurons. Agonists of this receptor (e.g. ipsapirone, a selective 5-HT1A receptor partial agonist) may inhibit food intake [23]. Another serotonin agonist is fenfluramine, which is used as an anti-obesity medication. Quetiapine, amitriptyline and trazodone are 5-HT1A antagonists, while buspirone, ziprasidone and aripiprazole - its agonists [24]. Thus, action at 5-HT1A receptors closely reflects metabolic profiles of these medications. However, clozapine is also 5-HT1A agonist and this antipsychotic has extremely orexigenic character. Many antidepressants acts via increasing concentration of serotonin in the synaptic cleft [25]. This may result in increased activity of postsynaptic 5-HT1A receptors. However, it is unclear how these changes translate into alterations of energy homeostasis since many antidepressants cause weight gain despite stimulation of 5-HT1A receptor. (b) 5-HT1B Blockade of this receptor causes increased activity of NPY neurons in the hypothalamus and consequently increased appetite [26]. Serotonin 5-HT1B receptor is probably responsible for increased appetite during treatment with lithium. Massot et al. have shown that lithium is the 5-HT1B ligand and its antagonistic properties may play some role in antidepressive action of lithium [27]. It is thought that this receptor may also play important role in appetite-stimulating properties of antipsychotics: chlorpromazine, clozapine, olanzapine, risperidone, quetiapine and sertindole (which are antagonists of 5-HT1B), while ziprasidone, antipsychotic of little effect on appetite and weight, is partial agonist of this receptor [28]. (c) 5-HT2A 5-HT2A receptor antagonism is a common property of many typical (e.g. chlorpromazine) and most atypical antipsychotics (including aripiprazole, which has a minimal effect on appetite and weight) [29]. Several antidepressants are also 5-HT2A antagonists, including mirtazapine, mianserin and trazodone [30]. 5-HT2A receptor agonists (e.g. TCB-2) reduce appetite and inhibit food intake [31]. There are however reports of the same activity for 5-HT2A receptor antagonists [32].

5 16 Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No. 1 Wysoki ski and K oszewska Therefore, it is difficult to unambiguously determine how affinity to 5-HT2A receptors affect orexigenic or anorexigenic properties of psychotropic medications. (d) 5-HT2B 5-HT2B is another serotonin receptor involved in appetite regulation. Receptors of this subtype are localized on AgRP/NPY neurons of ARC [22]. Activation of these receptors leads to hyperpolarization of cell membranes and inhibits secretion of orexigenic neuropeptides. Moreover, activation of 5-HT2B receptors reduces inhibitory effect on POMC neurons, which also intensifies anorexigenic activity. Activation of 5-HT2B and both mechanisms are responsible for appetite-lowering properties of fluvoxamine [33]. Two antipsychotics of very potent appetite-increasing properties (olanzapine and clozapine) are 5-HT2B antagonists, but so is aripiprazole. On the other hand, ziprasidone (which has a neutral metabolic profile, similarly to aripiprazole) is agonist of 5-HT2B receptor [29]. (e) 5-HT2C Fenfluramine and m-cpp are anorexigenic substances. Their mechanism of action includes agonistic properties at 5-HT2C receptor [34]. Activation of 5-HT2C receptors situated on POMC neurons of ARC leads to increased secretion of POMC, which in turn activates anorexigenic pathways [35]. Antagonistic properties at 5-HT2C receptors were found for chlorpromazine, olanzapine, clozapine, quetiapine, risperidone and sertindole [29]. These antipsychotics, via their antagonistic properties at 5-HT2C receptors, may disturb sense of satiety and increase appetite. On the other hand, aripiprazole, antipsychotic of dopamine and serotonin-stabilizing activity, is 5-HT2C partial agonist [36]. This may explain its favorable effect on appetite and body mass. However, another 5-HT2C antagonist is ziprasidone, which also has a favorable metabolic profile. 5-HT2C receptors also mediate weight gain induced by treatment with antidepressants. Contrary to antipsychotics, which cause rapid blockade of 5-HT2C, antidepressants from the group of selective serotonin reuptake inhibitor (SSRI) cause down-regulation of these receptors. It has similar consequences as for 5- HT2C antagonists. This mechanism is responsible for increased appetite and weight gain during treatment with paroxetine [37], which causes desensitization of 5- HT2C receptor [38]. Of all SSRIs, paroxetine causes most weight gain. Trazodone, mianserin and mirtazapine are also 5-HT2C receptor antagonists and may cause increased appetite and weight gain in this mechanism. Other Receptors (a) Histamine H1 Receptor In 1999 Wirshing et al. published a study which confirmed hypothesis that treatment-induced weight gain is proportional to affinity to histamine H1 receptor [39]. Two antipsychotics of the highest affinity to H1 receptor are clozapine and olanzapine. These observations were confirmed by Kroeze et al. who stated that affinity to H1 receptor is the strongest predictor of treatment-induced weight gain (Spearman's rank correlation coefficient = for H1 comparing to -0.54, and for alpha-1, 5- HT2C and 5-HT6 receptors, respectively) [40]. As it was demonstrated in animal studies, H1 receptor is required for leptin action. Morimoto et al. studied the effect of leptin in mice with knocked-out H1 receptor gene (H1R). No reduction of food intake was observed in these animals after administration of exogenous leptin [41]. H1 receptor may also mediate central activity of ghrelin. Blockade of H1 receptor activates AMP kinase (AMPK) in ARC and PVN. Similar actions are caused by ghrelin, while leptin inhibits AMPK activity in neurons of these hypothalamic nuclei. Activation of AMPK leads to the reversal of anorexigenic properties of leptin [42]. Activation of AMPK was observed in fragments of brain tissue coming from mice which had administered clozapine, olanzapine and quetiapine. On the other hand, ziprasidone, aripiprazole, haloperidol and risperidone did not cause changes in AMPK activity. Antagonistic properties at H1 receptors have also tricyclic antidepressants and mirtazapine, mianserin and trazodone [43]. This is one of the mechanisms underlying obesity induced by these medications. Another medication for which H1 receptor antagonism is associated with increased appetite, particularly for sweet foods, is hydroxyzine. All these examples demonstrate a significant role of H1 receptor in the development of treatment-induced obesity. However, it should also be noted that there are medications with no affinity to H1 receptor that increase appetite and body weight. (b) Alpha-1 Adrenergic Receptor Alpha-1 adrenergic receptor plays important role in appetite regulation. Activation of this receptor reduces

6 Increased Appetite and Weight Gain Induced by Psychotropic Medications Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No appetite and underlies anorexigenic properties of amphetamine and similar substances used in the treatment of obesity (e.g. synephrine, phenylpropanolamine, phentermine) [44]. Most antipsychotics have antagonistic properties at alpha-1 adrenergic receptor. Moreover, some antidepressants (e.g. amitriptyline, mirtazapine, trazodone, sertraline) are also alpha-1 antagonists [45]. Therefore, there is some convergence between this pharmacological property and orexigenic potential. (c) Dopamine D1 and D2 Receptors Interaction between dopaminergic neurons of mesolimbic system and orexin-producing neurons was found [46]. This interaction affects dopamine-mediated modulation of feeding behavior. Anorexigenic activity of amphetamine and its derivatives results from increased dopaminergic neurotransmission due to increased presynaptic release of dopamine. Moreover, in animal models dopamine administered into brain regulates appetite via bidirectional modulation of orexin neurons. When acting via D1 receptors dopamine activates orexin-synthesizing neurons, while activation of D2 leads to inhibition of these neurons [46]. Therefore, since antipsychotic activity is associated with antagonism at D2 receptor, all antipsychotics have native orexigenic potential. ROLE OF NEUROPEPTIDES Leptin Antipsychotics have diverse effects on various neuropeptides that participate in regulation of appetite. Not always these observations reflect real effect on weight gain for a given medication. Blockade of 5- HT2C receptor situated on ARC neurons by risperidone blocks the action of leptin, which results in increased amount of adipose tissue despite increased concentration of leptin [47]. This may indicate the presence of central leptin resistance. Disorders of leptin neurotransmission, via canceling out negative feedback, lead to lack of appetite suppression or regulation of energy utilization. Increased leptin concentrations also causes increased expression of the most potent orexigenic factor - NPY and may lead to insulin resistance, also linked with obesity. Similar results were found for other antipsychotics - olanzapine [48], clozapine and quetiapine [49] and sulpiride [50], but not for haloperidol [51]. Observed increase of leptin concentration was accompanied by weight gain. Ziprasidone caused significant reduction of serum levels of leptin in rats [52]. There is an excellent review of effects of antipsychotics on leptin and ghrelin levels published by Sentissi et al. [53]. In the majority of analyzed studies it was found that leptin levels are increased during treatment with olanzapine and clozapine. Results for risperidone were ambiguous. The authors did not found that first generation antipsychotics affect leptin levels. Some authors claim that changes in leptin levels are secondary to treatment-induced weight gain. Herran et al. compared group of patients with schizophrenia and healthy subjects matched by sex, age and BMI. They found no significant differences for leptin levels between both groups, but only in the patients group leptin levels were correlated with body weight and were higher in patients treated with olanzapine [54]. Results of studies on the effect of treatment with lithium on leptin levels are also inconclusive. In one study no changes were found after 4 weeks of treatment [55]. The authors of this study have also found that carbamazepine do not raise leptin levels. On the other hand, Armaca et al., while studying subjects with bipolar disorder, have found that after 8 weeks of treatment with lithium levels of leptin were significantly raised [56]. In both publications study groups were small (n = 25 and n = 15, respectively), so these results must be interpreted with caution. In larger (n = 98) study Uludag et al. confirmed that treatment with carbamazepine is not associated with increased levels of leptin [57]. It was found that leptin levels are increased during treatment with valproate [58]. Hamed et al., when studying children with epilepsy, did not find changes of leptin levels in subgroups taking lamotrigine and carbamazepine and found increased leptin levels in the subgroup on valproate [59]. Moreover, levels of leptin were correlated with dose of valproate and treatment duration, concentration of insulin (index of insulin resistance) and metabolic parameters (BMI, levels of LDL and HDL lipoproteins). Addition of topiramate to olanzapine caused significant reduction of body weight, lower leptin levels and improvement in lipid parameters in patients with schizophrenia [60]. Antidepressants may also increase concentration of leptin. Kraus et al. observed small raise of leptin in 11 patients with depression treated with mirtazapine. No such changes were found in 9 patients treated with venlafaxine [61]. Due to small number of study patients these results must be interpreted with caution. Hinze- Selch et al. have found no changes of leptin levels during treatment with tricyclic antidepressants (amitriptyline or nortriptyline, n = 12) and paroxetine (n = 9) [62]. Berligen et al. reported increased levels of

7 18 Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No. 1 Wysoki ski and K oszewska leptin during treatment with amitriptyline [63]. However, they studied patients with migraine (n = 49), without depression and therefore we do not know how these results can be extrapolated to population of patients with mental disorders. In the study on rats no effect of treatment with fluoxetine on leptin levels was found [64]. Observed diverse effects of antipsychotics, antidepressants and mood stabilizers on leptin levels confirm that different medications have different mechanisms of increasing appetite and weight gain. Equally important is the observation that observed changes cannot be solely attributed as secondary to treatment-induced weight gain, which was demonstrated in several analyses, e.g. by Jin et al. [65]. This study shows that different medications may trigger primary changes in leptin expression and secretion by adipose tissue. This may be confirmed by the observation by Sentissi et al. which indicates that leptin levels become raised very quickly after initiating treatment with olanzapine or clozapine, even before significant weight gain occurs [53]. Ghrelin Antipsychotics also affect serum levels of ghrelin. It was observed that levels of ghrelin are raised in patients treated with risperidone risperidone [47], olanzapine [66], clozapine and, interestingly, amisulpride [67]. In the last of these studies, Esen- Danaci et al. found that levels of ghrelin in patients treated with quetiapine did not differ from control subjects, but also the highest ghrelin levels were found in the subgroup taking amisulpride. This indicates there are complex and diverse mechanisms underlying treatment-induced weight gain and increased appetite. Palik et al. compared 4 groups of patients with schizophrenia taking clozapine, olanzapine, risperidone and quetiapine with healthy subjects. In this study it was found that levels of ghrelin were significantly higher in all four groups comparing to control subjects. No changes were found between individual antipsychotics [68]. The same antipsychotics were studied by Birkas Kovats et al. [69]. Their results were similar to results found by Palik et al. On the other hand, review published by Sentissi et al. [53] indicates that several results are inconclusive as some studies found decreased levels of ghrelin during treatment with antipsychotics. This applies mainly to olanzapine, which may result from the fact that this medication was studied most often (five out of eight analyzed studies). Few studies have been published on changes of ghrelin levels in the course of treatment with antidepressants. Barim et al. studied whether treatment with citalopram (in dose 40 mg/day) normalizes reduced level of ghrelin in patients with depression. After three months of treatment no changes in levels of acylated and deacylated were found comparing to baseline values [70]. Schmid et al. reported effects of short-term (28 days) treatment with mirtazapine on various endocrine parameters, including levels of ghrelin and leptin [71]. Besides significant and rapid weight gain (average weight gain was 3 kg), reduced levels of ghrelin and increased levels of leptin were reported. These changes may be secondary to changes of body weight. Fujitsuka et al. studied effects of fluvoxamine, fluoxetine and paroxetine on gastrointestinal tract activity of rats. They have found that increased peristaltic activity was accompanied by reduction of acylated ghrelin levels induced by antidepressants [72]. It was also found that serotonin 5- HT2C receptor is involved in this processes since when 5-HT2C antagonist was applied, both effects were blocked. Martin et al. did not find changes of ghrelin levels during treatment with valproate [73]. On the other hand, Cansu et al. found that ghrelin levels were reduced in 18 children with epilepsy treated with valproate [58]. However, according to these researchers observed changes may be secondary to weight gain induced by other neuropeptides (leptin, galanin, NPY), which levels were found to be increased in the study group. Other Neuropeptides Increased appetite for sweet foods often occurs in the beginning of treatment with antidepressants (often also with antipsychotics and mood stabilizers). In the 1970s Paykel coined the term carbohydrate craving, which describes this phenomenon very accurately. As it was demonstrated, it results from increased synthesis of NPY [74], which occurs during treatment with various psychotropic medications. There is a clear correlation between the effect of psychotropic medications on NPY levels and their orexigenic potential. Both clozapine [75] and olanzapine [76] increase expression of NPY in the hypothalamus. Such changes were not observed for haloperidol [75]. Increased levels of NPY are also present during treatment with lithium and SSRI antidepressants [77] and valproate [58]. Topiramate, which does not increase appetite, also increases NPY levels. However, topiramate simultaneously increases

8 Increased Appetite and Weight Gain Induced by Psychotropic Medications Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No levels of CRH in the hypothalamus, which is thought to cancel out behavioral effects of NPY and to normalize appetite, while preserving anti-epileptic activity of topiramate (via increased levels of NPY) [78]. Expression of CART, which is a neuropeptide of anorexigenic properties, is stimulated by dopamine. Beaudry et al. demonstrated that clozapine inhibits the expression of CART. Such reaction was not observed for haloperidol, which has very little orexigenic activity. Dopamine D3, but not D2, receptors mediate this process [79]. We do not know whether other selective D3 receptor antagonists (amisulpride, sulpiride) have also such activity. Fadel et al. examined activation of c-fos protein (marker of neuronal activity) in orexin-releasing neurons of LHA. They have found that clozapine triggers induction of c-fos protein in 75% of orexigenic neurons, while amphetamine triggered such activity in less than 1/3 of these neurons [80]. The authors stated that this may indicate that there is additional mechanism that mediates clozapine-induced weight gain. Activation of c-fos protein in orexigenic neurons was also found for olanzapine [81]. ROLE OF NEUROENDOCRINE SYSTEM Prolactin Hyperprolactinemia, irrespective of its causes, may lead to obesity [82]. Many psychotropic medications may increase levels of prolactin [83], but it is particularly frequent during treatment with antipsychotics (antagonists of D2 receptor at lactotropic cells cancel out inhibitory effect of dopamine on prolactin secretion from the anterior pituitary gland). This applies particularly to risperidone (it causes the highest increase of prolactin levels of all antipsychotics), sulpiride and amisulpride and first generation antipsychotics. Antidepressants may also cause hyperprolactinemia. This is particularly true for clomipramine, amitriptyline, citalopram, paroxetine and fluvoxamine [84]. There are single reports of hyperprolactinemia induced by treatment with alprazolam, buspirone and moclobemide. Levels of prolactin may be reduced during treatment with lithium (even to 40%) [85] and aripiprazole (less effect comparing to lithium) [86]. It is not clear whether hyperprolactinemia leads to obesity via increased appetite or via different mechanisms. Prolactin may cause glucose intolerance and insulin resistance. Tuzcu et al. demonstrated that these changes are not secondary to obesity and changes in gonadal and adrenal steroid hormones [87]. Moreover, hyperprolactinemia may have a direct effect on appetite. Gonadal and adrenal steroid hormones may be involved in this process. The state of hyperprolactinemia is associated with reduced synthesis of estrogens and increased synthesis of androgens [88]. Therefore, a balance between estrogens/ androgens is moved towards hormones of orexigenic properties (androgens). Additionally, lowered levels of progesterone during hyperprolactinemia may lead to the development of abdominal obesity [89]. This may be associated with inhibitory effect of progesterone on the activity of glucocorticoids at adipose tissue [90]. Results of animal studies also show that hyperprolactinemia plays important role in obesity induced by other antipsychotics. In rats sulpiride-induced obesity was prevented by bromocriptine (via normalization of prolactin levels) [91]. Insulin Insulin resistance is glucose metabolism abnormality in which cells (myocytes, adipocytes, hepatocytes) fail to respond to the normal actions of insulin. Insulin resistance develops in the course of abdominal obesity, buy may also trigger its development (some evidences come from observations of patients who lost weight during treatment with metformin - anti-diabetic medication that normalizes sensitivity to insulin) [92]. The development of insulin resistance may also be an adaptive mechanism, which prevents further weight gain in obese patient [93]. Protective action of insulin resistance results from lowering peripheral anabolic properties of insulin and increasing levels of insulin in the brain, which reduces appetite and increases energy utilization. However, in women hyperinsulinemia resulting from insulin resistance stimulates secretion of testosterone, which (as was described above) promotes development of abdominal obesity via increased levels of androgens. Insulin resistance develop during treatment with many psychotropic medications. This is particularly often in case of second generation antipsychotics (olanzapine, clozapine, quetiapine, and - to less extent - risperidone) [94]. A very large (n = 165,958) study by Andersohn et al. demonstrated that antidepressants may also increase the risk of diabetes via development of insulin resistance [95]. This particularly applies to tricyclic and tetracyclic antidepressants, while risk associated with SSRIs is lower (citalopram seems to be

9 20 Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No. 1 Wysoki ski and K oszewska the safest of this subgroup [96] and therefore - probably also escitalopram). The risk was present only in cases of long-term treatment with medium or high doses. Increased risk of diabetes and insulin resistance was also observed in patients treated with valproate [97]. For valproate it was not possible to determine the direction of association between obesity and diabetes. It cannot be excluded that insulin resistance was secondary to obesity and not its cause. OTHER MECHANISMS Resting Metabolism In some cases weight gain in the course of pharmacotherapy does not result from increased appetite. Paradoxically, some patients have weight gain even if their appetite is lower comparing to pretreatment. This phenomenon can be explained by treatment-induced changes of resting metabolism. Resting metabolic rate (RMR) is the amount of energy expended at rest, in normal climatic conditions. This energy is used for the functioning of the vital organs and forms up to 70% of energy expenditure. Therefore, chronic changes of BMR may translate into energy surplus and as a result - into weight gain. It seems that medications that cause weight gain in the mechanism of reducing BMR are mainly tricyclic antidepressants [98]. Fernstrom et al. first described reduction of BMR by 17-24% in 3 female patients taking imipramine, tranylcypromine (monoamine oxidase (MAO) inhibitor) and combination of tranylcypromine with amitriptyline. This reduction was associated with weight gain up to 3.5 kg during the study [99]. Opposite activity was described for fluvoxamine - in patients taking this antidepressant increased BMR by 24-40% and weight loss by kg were described [100]. No effect for fluoxetine - other antidepressant of the SSRI group - on BMR was found [101]. In this study fluoxetine (doses up to 60 mg/day) was used in 30 obese patients as weight-loss drug. The authors stated that observed weight loss (on average 1.16 kg) results from other mechanisms of fluoxetine. Similar results were observed for desipramine [102]. Fifty six patients with panic attacks participated in this study, half of them were taking placebo. Significant weight loss was observed in the desipramine group, but no changes of BMR were found, while in the placebo group neither body weight nor BMR changed. It indicates that this mechanisms applies to only some antidepressants. No changes of BMR were found during treatment with carbamazepine. However, it seems that weight gain observed during treatment with this drug may be associated with significant reduction of thyroxin levels [103]. Results for antipsychotics are equally diverse as for antidepressants. In small (n = 20) study of 4-week treatment with olanzapine no association between weight gain (average 3.8 kg) and changes of BMR (24.7 kcal/kg vs kcal/kg pre- and post-treatment, respectively) [104]. Moreover, no changes of BMR were found in patients taking haloperidol. Fountaine et al. also did not find that olanzapine-induced weight gain is associated with changes in energy expenditures and results mainly from increased appetite and food intake [105]. Procyshyn et al. have found that during 1-month treatment with clozapine BMR value was reduced by %, which was associated with weight gain ranging from 2.9 to 9 kg; moreover, weight gain was proportional to reduced BMR [106]. Important limitation of this observation is the fact that only three subjects participated in this study. TNF- Although TNF- cytokine has anorexigenic properties [107], several studies show its participation in treatment-induced obesity [69]. Mechanisms of this phenomenon are unknown. Levels of TNF- are raised in obese subjects [108]. Moreover, animal studies indicate that TNF- may participate in the development of insulin resistance: neutralization of TNF- in rats with genetically determined obesity caused increased cell sensitivity to insulin and improved intracellular glucose transportation [109]. Activation of TNF- cytokine was found for many medications that induce weight gain (clozapine, olanzapine, amitriptyline, mirtazapine, lithium) [51, 62, 110], and was not observed for medications that have no effect on body weight (haloperidol, venlafaxine) [61]. The only exception here is paroxetine (which may cause significant weight gain), for which no activation of TNF- was found. Activation of the TNF- system occurs early in the course of the treatment and thus it might be an early and sensitive marker of ensuing weight gain [62]. OTHER MECHANISMS Besides discussed above neurobiological mechanisms of appetite changes in the course of treatment with psychotropic medications, there are several additional processes, which cannot be clearly

10 Increased Appetite and Weight Gain Induced by Psychotropic Medications Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No attributed to individual mechanisms. One of them is excessive drinking of sweet (and thus highly caloric) beverages which in some cases is caused by dry mouth. Its main mechanism is antagonism at M1 muscarinic receptor. Thus, this problem is particularly significant for medications of anticholinergic activity, i.e. tricyclic antidepressants and various antipsychotics (chlorpromazine, levomepromazine, flupentixol, zuklopentixol, clozapine, olanzapine and quetiapine) and antidepressants (fluvoxamine, mianserin, trazodone, reboxetine, moclobemide and bupropion). Increased thirst and polydipsia is often present in patients on lithium. Lithium also causes abnormalities in thyroid cells functioning due to accumulation of lithium in these cells, which results in reduced coupling of iodine, structural changes of thyroglobulin and inhibition of thyroid hormones secretion [111]. These lead to hypothyroidism, which prevalence in patients treated with lithium is up to 10% (in women of middle age who start treatment with lithium it may be even two times higher). This results in reduced metabolism and weight gain (primarily due to accumulation of water and sodium). Fluid retention may also underlie weight gain associated with carbamazepine, although we do not know its mechanism [112]. Moreover, during treatment with clozapine the hypothalamic-pituitary-adrenal axis becomes activated, which results in increased levels of cortisol [113]. Carbamazepine may also increase levels of total cholesterol, LDL lipoproteins and triglycerides [114]. These are probably caused by reduced synthesis of thyroid hormones [103], which leads to changes in conversion pattern of intermediate density lipoproteins (IDL]. ROLE OF GENETIC POLYMORPHISMS Table 2: Role of Genetic Polymorphisms in weight Gain Induced by Antipsychotics The results of GWAS studies, as well as studies of 5-HT2C receptor, leptin and its receptor, H1, alpha1 and D2 receptors and other genes involved in the regulation of metabolism and body weight indicate a multigene character of this phenomenon. Moreover, the role of particular polymorphisms seems to be specific for individual antipsychotics. However, so far attempts to establish polymorphisms responsible for treatmentinduced weight gain were unsuccessful. Numerous studies have significant methodological limitations, thus restricting a possibility to generalize their results. Many studies analyzed the role of single nucleotide polymorphisms (SNP) in the development of obesity induced by psychotropic medications, but also in other metabolic abnormalities observed in patients taking these medications. The majority of data applies to antipsychotics. Table 2 shows a summary of the role of genetic polymorphisms in weight gain induced by antipsychotics. We did not included studies that focused on other metabolic abnormalities (e.g. dyslipidemia, insulin resistance). Study Gene/polymorphism AP(s) Results [123] [124] 492,000 SNPs CLO, RIS, OLA, QUE, ZIP, PERF 31 genes, 1084 SNPs CLO, OLA, QUE, RIS, ZIP, PERF MEIS2 rs : BMI, WHR, HA risk for RIS KCNJ11 rs allele T: BW SLC30A8 rs allele G: BW FTO rs allele C: BW [125] HTR2C: rs6318 (68G>C, Ser23Cys) HTR2A: CAn polymorphisms HTR1A: T102C, His452Tyr HR1: non-functional promoter polymorphisms HR2: G1018A ADRA1A: rs (Arg347Cys) ADRB3: rs4994 (Trp64Arg) CYP1A2: C A in intron 1 TNFA: G-308A CLO genotype HTR2C rs6318(ser;ser) in women or allele 23Ser in men: BW genotyp ADRA1A rs (cys;cys): BW genotype ADRB3 rs4994(trp;trp): BW genotype TNFA -308A/A: BW [126] [127] 10 genes, 15 SNPs RIS genotypes 5HT2A 102T/C, 5HT2C rs (c;t), 5HT6 267C/T, BDNF 66Val/Met, CYP2D6 188C/T: BW 21 SNPs OLA allele HTR2A 102T, GNB3 825T, HTR2C 23Cys: BW genotype ADRB3 64Arg/Arg: BW

11 22 Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No. 1 Wysoki ski and K oszewska Table 2 Continue Study Gene/polymorphism AP(s) Results [118] HTR2C: rs (-759C/T) MIX allele HTR2C -759C: BW [120] HTR2C: rs (-759C/T) CLO allele HTR2C -759T: BW [116] HTR2C: rs (-759C/T) OLA allele HTR2C -759T: BW [121] HTR2C: rs (-759C/T), rs (-697G/C) OLA allele HTR2C -759T and HTR2C -697C: BW [117] HTR2C: rs (-759C/T) CLO allele HTR2C -759T: BW [128] HTR2C: rs (-759C/T) MIX allele HTR2C -759T: BW [129] HTR2C: rs (-759C/T), rs (-697G/C), rs (-1165A/G), rs6318 (c.68g>c, Ser23Cys) MIX allele HTR2C -759C: BW [130] HTR2C: rs (-759C/T), rs (-697G/C), rs6318 (c.68g>c, Ser23Cys) HTR2A: -1438A>G, 102T/C, His452Tyr OLA, CLO haplotype HTR2C [-759C, -697C, 23Ser]: BW for OLA vs. [-759T, - 697C, 23Cys] haplotype HTR2C [-759C, -697G, 23Cys]: BW for CLO [131] HTR2C: HTR2C:c (GT)n, rs (-997G/A), rs (-759C/T), rs (-697G/C), rs (C>G) MIX rs518147, rs , HTR2C:c (GT)n: risk of MeS [132] HTR2C: HTR2C:c (GT)n, rs (-997G/A), rs (-759C/T), rs (-697G/C), rs (C>G) MIX HTR2C:c (GT)n, rs : risk of MeS rs allele C: risk of MeS for CLO and RIS [133] HTR2C: rs6318 (c.68g>c, Ser23Cys), rs (-759C/T), (GT)12-18/(CT)4-5 motif MIX no effect [134] HTR2C: rs (-759C/T) CLO no effect [135] HTR2C: rs (-759C/T) OLA no effect [136] HTR2C: rs (-759C/T) MDR1: rs (2677G>T), rs (3435C>T) OLA, RIS genotype HTR2C rs (c;t): no effect allele HTR2C 2677T and 3435T: BW for RIS [137] HTR2C: rs521018, rs498177, rs , rs , rs , rs6318 (c.68g>c, Ser23Cys) CLO, OLA, RIS genotype HTR2C rs498177(c;c): risk MeS for CLO in women [138] HTR2C: rs (-759C/T), rs (-997G/A), rs (-1028GT12/GT15/16), rs (-1165A/G) - allele -759C: expression of HTR2C [139] HTR2C: rs (-1165A/G), rs (-997G/A), rs6318 (c.68g>c, Ser23Cys), rs (-759C/T) INSIG2: rs , rs , rs , rs MIX HTR2C rs498207, rs , rs : BW LEP: rs [140] INSIG2: rs OLA, QUE, RIS, ZIP, CLO, PERF no effect [141] 44 SNPs MIX INSIG2 rs , rs , rs : BW [142] INSIG2 rs , rs , rs , rs CLO, RIS, OLA, HAL no effect [143] HTR2C: rs (-759C/T) LEP: rs (G-2548A) CLO, OLA, RIS, AMI, FGA, MIX combination of genotypes HTR2C rs (c;c) and LEP rs (a;a): BW

12 Increased Appetite and Weight Gain Induced by Psychotropic Medications Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No Table 2 Continue Study Gene/polymorphism AP(s) Results [119] HTR2C: rs (-759C/T) LEP: rs (G-2548A) MIX allele HTR2C -759T: BW genotype LEP rs (a;g): BW [144] LEP: rs (G-2548A) LEPR: rs (Q223R) MIX allele LEPR 223R: BW [145] LEP: rs (G-2548A) LEPR: rs (Q223R) HTR2C: rs (-759C/T) MIX allele LEPR 223R: BW [146] LEP: rs (G-2548A) OLA genotype LEP rs (a;a): BW [147] [148] LEP: rs (G-2548A) RIS, CHP genotype LEP rs (a;a): BW, amount of subcutaneous fatty tissue LEP: rs (G-2548A) CLO genotype LEP rs (a;a): initial BMI genotype LEP rs (g;g): initial BMI [149] LEP: rs (G-2548A) RIS, CHP genotype LEP rs (a;a): BW [150] LEP: rs (G-2548A) CLO genotype LEP rs (a;a): BW in men [151] LEP: -1548G/A LEPR: rs (Q223R) OLA 1 allele G in both genes + [OLA] >20.6 ng/ml: BW [152] 4 genes, 14 SNPs OLA genotype LEP rs (c;g): BW [153] FTO: rs SH2B1: rs LEP: rs LEPR: rs HAL, OLA, RIS, ZIP, ARI, QUE genotype FTO rs (a;a): higher BW before treatment [154] HR1: rs346070, rs M3R: rs CLO, RIS, OLA, QUE, ARI, MIX, FGA haplotype HR1 rs rs A-T: increased risk of BW for CLO, OLA, QUE [155] HR1: Glu349Asp CLO no effect [156] ADRA2A: rs (-1291C>G) CLO genotype ADRA2A rs (c;c): BW in Asians [157] ADRA2A: rs (-1291C>G) CLO, OLA allele ADRA2A -1291C: BW in Europeans [158] ADRA2A: rs (-1291C>G) OLA allele ADRA2A -1291G: BW in Asians [159] DRD2: rs (-141C ins/del) RIS, OLA DRD2 rs del: BW [160] DRD2: rs (Taq1A) DRD3: rs6280 (Ser9Gly) OLA, RIS, QUE DRD2 rs variant A1: [PRL] [161] PPAR: Pro12Ala OLA genotype PPAR Pro/Ala: BW [162] GNB3: rs5443 (825C/T) CLO genotype GNB3 rs5443(t;t): BW [163] GNB3: rs5443 (825C/T) ADRB3: Trp64Arg CLO no effect [164] GNB3: rs5443 (825C/T) OLA no effect [165] 29 SNPs, 13 genes OLA, RIS genotype APOA4 rs5092(a;g) or (A;A): BW for OLA genotype APOE rs7412(c/c) or (C;T): BW for OLA genotype SCARB1 rs (c;c) or (C;T): BW for OLA genotype LEPR rs (c;g) or (G;G): BW for RIS genotype PON1 rs705381(c;t) or (T;T): BW for RIS genotype Y5R rs (a;g) or (G;G): BW for RIS [166] CNR1: 20 SNPs CLO, OLA, RIS, HAL CNR1 rs allele T: BW for CLO, OLA [167] CNR1: rs (1359G/A) FAAH: 385C/A (Pro129Thr) CLO, OLA, RIS, QUE, HAL allele FAAH 385A: BW

13 24 Journal of Advanced Clinical Pharmacology, 2014, Vol. 1, No. 1 Wysoki ski and K oszewska Study Gene/polymorphism AP(s) Results Table 2 Continue [168] MC3R: rs PER2: rs SDC3: rs , rs LEPR: rs NR3C1: rs6190, rs6195, rs6196 (N766N), rs MIX NR3C1 rs6196 allele G: BMI, WHR [169] MTHFR: rs (A1298C), rs (C677T) MIX allele MTHFR 1298C: risk of MeS [170] MTHFR: rs (A1298C), rs (C677T) MIX allele MTHFR 677T: risk of MeS [171] TNFA: rs (-308G>A) CLO genotype TNFA rs (g;g): BW [172] SERT: SERTPR l/s, SERTin2 l/s OLA genotype SERTPR l/s or s/s in women: BW [173] PMCH: rs (-4825A/G), rs MIX allele PMCH -4825G: BW for OLA (age <50) [174] HTR2C: rs (-759C/T) MDR1: rs (2677G>T), rs (3435C>T) OLA, RIS allele HTR2C -759T: risk of obesity [175] SNAP-25: DdelI, MnlI, TaiI CLO, OLA, RIS, HAL no effect [176] 12 SNPs of CCK, CCKA, CCKB MIX genotype CCKB rs (a;a): BW for CLO lub OLA ADRA1A - adrenergic receptor 1A; ADRA2A - adrenergic receptor 2A; ADRB3 - adrenergic receptor 3; AGT - angiotensinogen proteinase inhibitor; APOA4 - apoliprotein A4; APOE - apoliprotein E; CCK - cholecystokinin; CCKA - cholecystokinin receptor A; CCKB - cholecystokinin receptor B; CNR1 - cannabinoid receptor 1; CYP1A2 - P450 1A2 cytochrome; CYP2D6 - P450 2D6 cytochrome; DRD2 - dopamine receptor D2; DRD3 - dopamine receptor D3; FAAH - fatty acid amide hydrolase; FTO - fat mass and obesity associated; GNB3 - protein G subunit beta-3; HR1 - H1 histamine receptor; HR2 - H2 histamine receptor; HTR1A - 5-HT1A serotonin receptor; HTR2A - 5-HT2A serotonin receptor; HTR2C - 5-HT2C serotonin receptor; INSIG2 - insulin-induced gene 2; KCNJ11 - Potassium Channel Inwardly Rectifying Subfamily J Member 1; LEP - leptin; LPL - lipoprotein lipase; M3R - muscarine receptor M3; MC3R - melanocortin receptor 3; MDR1 - multidrugresistant protein; MEIS2 - Meis homeobox 2; MTHFR - methylenetetrahydrofolate reductase; NPY - neuropeptide Y; NR3C1 - nuclear receptor subfamily 3, group C, member 1; PER2 - period 2; SDC3 - syndecan 3; PMCH - pro-melanin-concentrating hormone; PON1 - paraoxonase 1; PPAR - peroxisome proliferator-activated receptor; SCARB1 - scavenger receptor class B member 1; SERT - serotonin transporter; SERTin2 - intron2 variants of SERT; SERTPR - promoter variants of SERT; SH2B1 - Src homology 2; SLC30A8 - Solute carrier family 30 member 8; SNAP-25 - synaptosomal-associated protein of 25 kda; TNFA - tumor necrosis factors TNF- ; Y5R - NPY receptor Y5. AP(s) - antipsychotic(s); AMI - amisulpride; ARI - aripiprazole; CHP - chlorpromazine; CLO - clozapine; FGA - first generation antipsychotics; HAL - haloperidol; MIX - various; PERF - perphenazine; QUE - quetiapine; RIS - risperidone; ZIP - ziprasidone. [] - concentration; BMI - body mass index; HA - hypertension; BW - body weight; MeS - metabolic syndrome; PRL - prolactin; WHR - waist to hip ratio. HTR2C (serotonin 5-HT2C receptor) is the most studied gene. This gene is situated on the chromosome X and thus inheritance of its alleles is different in men and women. Several studies confirm that mutations of this gene may be associated with obesity [115]. Moreover, several studies show that there might be a relationship between polymorphisms of the HTR2C gene and antipsychotic-induced weight gain [ ]. The presence of -759C allele in rs SNP polymorphism (-759C/T) of the HTR2C gene is one of the most commonly cited loci for antipsychotic-induced weight gain [118]. Reynolds et al. have also confirmed in a group of 32 Chinese patients that the presence of - 759T allele is associated with significantly less weight gain during 6-week treatment with clozapine [120]. Ellingrod et al. have found that the presence of -759T allele may protect from olanzapine-induced weight-gain [116]. Forty two subjects in acute schizophrenic psychosis participated for 6 weeks in this study. Doses of olanzapine was up to 20 mg/day. This analysis demonstrated that the percentage of patients who did not have significant (defined as 10%) weight gain was significantly lower in T allele carriers comparing to C allele carriers (0/15 (100%) vs. 11/27 (40.7%), p = , respectively). Godlewska et al. have also found protective effect of the -759T allele (body weight of no patient with this allele increased 10%) and allele C in rs SNP polymorphism (-697G/C) of the HTR2C gene - only 3 out of 51 patients with this polymorphism had weight gain 10% [121]. Important advantage of the study is that patents with first episode of psychosis, previously untreated with antipsychotics (n = 36) and during the study they were on monotherapy with olanzapine. Similar results were obtained by Miller et al. In the group of 41 patients with treatment resistant schizophrenia the percentage of carriers of the -759T allele was significantly higher in the group with weight gain <7% after 6 moths of treatment with clozapine comparing to the group with higher weight gain [117].