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Antipsychotic drugs and Obesity

Ang Yee Shuen(presangle@gmail.com), A Yar Kyaw Zaw Hein (ayarhein80@gmail.com) Hnin Ye Pyone(hninyepyone@gmail.com),Tan Hui Yuan(tanhuiyuan1@gmail.com) Zaw Myo Tun(sgyi.mic@gmail.com) Abstract
Amongst the factors causing obesity, antipsychotics drug is becoming important one due to its increased use in mental illness. Second generation or atypical antipsychotic drugs has become preferable prescribing drugs for schizophrenic patients because of it has no extrapyramidal symptoms. But these can cause obesity and its fatal consequences by their various affinity on various receptors cause the abnormal response to some hormones and neuropeptides by higher center of the brain, that leads to disintegration of energy homeostasis. Recent studies state that TGF-beta/SMAD3 signaling pathway and genetic polymorphisms comes into important roles in APD induced obesity.

2.2 Receptors and neuropeptides interactions


The receptors of interest include serotonin 5-HT2A , 5-HT2C and 5-HT6 receptors , histamine H1 receptor, 1-2and 3 adrenergic receptors , muscarinic M3 receptors and dopamine D1, D2, D3 receptors.
Receptors
Serotonin 5HT2A 5HT2C 5HT6 Dopamine D1, D2, D3 Histamine H1 (Clozapine, Olanzapine) Adrenergic 1, 2 1/2/3 Muscarinic M3 (Olanzapine) Cannabinoid Peptide hormones Orexigenic neuropeptide Y AGRP Anorexigenic POMC Ghrelin Leptin
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2.4 Genetic polymorphisms


Genetic polymorphisms that are found to be associated with obesity and use of ASDs (1)-759/ T polymorphism, along with some other promoter region polymorphisms of the 5-HT2C receptor gene linked with protected from substantial weight gain (2) -2548A/G polymorphism, leptin gene, genotype -2548GG associate with increase incidence of weight gain. (3) Leptin receptor ( LEPR ) Q223R polymorphism may be associated with obesity in women. (4) Leptin gene -2548 G/A variant appeared to moderate the weight altering effect of risperidone. (5) FAAH cDNA 385C/A SNP for cannabinoid receptor associated with increase weight gain (6) Two polymorphisms ( 64 Arg allele and 825 T allele) of the 3 adrenergic receptor were associated with weight gain. (7) Arg 347Cys polymorphism of the alpha adrenergic receptor gene associated with increase weight gain. (8)The rs 471426 SNP, a variant in the leptin gene, was moderately associated with median weight gain (9)Melanocortin -4 receptor ( MC4R) gene, which is known to be linked to obesity.

Stimulation
Feeding,satiety Feeding Feeding

Inhibition
Feeding Feeding Feeding

Knockout model

Remarks
5HT2C antagonists (APD)attenuate reduction in food intake induced by leptin(leptin resistance) Obese -D2 receptor availability in brain

1. Introduction
Epidemic of obesity is the greatest public health crisis facing the UK. One in four adults in England is obese, and the figures are predicted to rise to 60% of men, 50% of women and 25% of children by 2050. Among the causes of obesity, the increasing use of Antipsychotic (neuroleptic) drugs was found to have strong correlations. Antipsychotic (neuroleptic) drugs are important therapeutic options for individuals with schizophrenia and other psychoses. We are proposing some of the possible links between Antipsychotic drugs and Obesity.

Obese Resistance to dietary induced obesity

Feeding Feeding Weight gain

H1 receptors on area of brains involved in energy homeostasis. affinitywt gain 1-noradrenergic binding was inversely proportional to body weight gain receptor occupancy with H1 receptor occupancy Olanzapine decrease binding CB1receptors in brainstem

2. Discussion
Weight gain can either be an increase in muscle mass, fat deposits or excess fluids such as water. Increase deposition of fats occur whenalthough energy and energy expenditure is imbalanced where intake not intake perfect, concordance in these rank estihormonal systems, etc.). Thus, APDsenergy could induce weight is more than energy expenditure.mates of weight gain liability with those outlined above. gain by direct or indirect actions on a number of interIn summary, in short-term studies there is a reasonable consensus that novel APDs can probably be classified into the following categories: (i) drugs inducing marked weight gain (olanzapine and clozapine); (ii) drugs inducing intermediate weight gain (sertindole, risperidone and quetiapine); (iii) drugs inducing minimal weight gain (ziprasidone); and (iv) drugs for which only limited data are available (zotepine and amisulpride), although amisulpride has been reported to have limited ability to induce weight gain [31], and zotepine probably induces substantial weight gain [32]. To these agents we must add the very novel atypical APD aripiprazole (abilify) [33], which in very short-term studies (46 weeks) was reported, at clinically effective doses, to induce statistically significant, but very limited, weight gain of approximately 1 kg [34], so this APD may prove to be essentially weight neutral. A recent important Cconsensus Statement on novel APDs accords with the categorization outlined here [21]. Clearly, novel APDs differ in their ability to induce weight gain. An adequate account of the mechanism(s) causing weight gain will obviously have to explain the important differences observed between these drugs. acting systems, as shown in figure 1. In recent years, it has been recognized that the behavioural, neural and endocrine systems involved in weight regulation are all extraordinarily complex. Thus analysis of the mechanism(s) involved in APD-induced weight gain requires research at various levels of analysis and an integration of work at these different levels. This is clearly a formidable challenge. Analyses of relevant mechanisms are complicated further by the fact that drug effects leading to weight gain may show tolerance. Thus, conclusions drawn from short-term studies should only be extrapolated to the long-term use of APDs with caution. For example, although quetiapine induces weight gain following shortterm treatment (vide supra), after 6 months treatment this drug may be weight neutral [35,36], implying that tolerance may have developed to its weight-enhancing action.
RA Antipsychotic-induced weight gain A. J. Goudie et al.

Feeding Triple knockoutobesity Feeding Feeding Functions Feeding Feeding Food intake and adiposity Weight
PART 3

2.5 General pathways that lead to anti-psychotics induced weight gain

feeding

Remark APDs activate hypothalamic orexin neurones (which stimulate food intake) to an extent correlated with their ability to induce weight gain . Clozapine has been reported to reduce the expression of the anorexigenic neuropeptide Olanzepine cause secretion of ghrelin ,induce apeptite and weight gain.

Unemployment,+Low+ socioeconomic+status,+ associated+ comorbi#dies+ Moderators+

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Baseline+ Metabolism+ Baseline+ diet+

Baseline+ ac#vity+

Increased leptin or other hormones triggered by overfeeding produced inhibitory effect on feeding behaviour. Olanzapine cause decrease level of insulin and leptin, associate with Neuropharmacology of Neural Systems and Disorders weight gain. Insulin resistance is associated with physiological binding and function in obesity. rat striatum. Such studies changes maintaining identified two major dopamine binding sites, termed Insulin resistance caused by SGA result in leading to obesity D and D . Although some older antipsychotic drugs, such
1 2

Drug+eects+
Dosage+and+ Dura#on+of+ treatment+

Insulin

glucose level
in dopamine release in the striatum and thereby to an increase in dopamine breakdown products such as HVA. Effects of antipsychotic drugs on D2 dopamine receptors The dopamine hypothesis of antipsychotic drug action was bolstered by studies of dopamine receptor

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Characterization of Weight Gain Induced by Olanzapine

Relationship between clinical potencies of antipsychotic medications (as measured by therapeutic dose) and their affinities for various receptors.
100

as chlorpromazine, are potent antagonists of both receptor types, antagonism of the D2 receptor correlates with antipsychotic efficacy 166 . Haloperidol, for example, a

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Average clinical daily dose (micromoles per kilogram)

APDs can affect these parameters in various ways (eg. By inducing sedation, changing metabolic rate, stimulating appetite or inhibiting satiety, altering food preferences, affecting hormonal systems, etc). Thus, APDs could induce weight gain by direct or indirect actions on a number of interacting systems. The extent of weight gain apparently varies by drug, which may be because of the drugs, differing degrees of action on the serotonergic, dopaminergic, cholinergic, histaminergic and other neurotransmitter systems.

To analyse the mechanism(s) mediating weight gain, we clearly need to define the phenomenon. Surprisingly, there have been relatively few empirical studies of APD-induced weight gain (as opposed to clinical trials) Mechanism(s) Involved in APD-induced Weight [37], and many such studies are small scale ones. OlanGain zapine has been studied much more extensively than all other APDs, due to the fact that it has been widely preUnderstanding such mechanism(s) requires that we map scribed and that it induces marked weight gain. Olanzathe pharmacology of APDs, which, as described below pine-induced weight gain is associated with enhanced can be very complex, onto the many systems involved in appetite [24,38], increased food intake and adiposity [7]. weight regulation. It is, therefore, perhaps unsurprising Olanzapine-induced hyperphagia is observed in the that, to date, there is no consensus on the mechanism(s) absence of any change in dietary composition [39]. ANTIPSYCHOTIC-INDUCED WEIGHT GAIN involved [21]. Weight gain occurs when energy expendSuch effects of olanzapine have been suggested speculaiture is less than the energy intake. APDs can affect tively to be due to drug-induced binge-eating disorder these Change parameters in Taking various ways TABLE 4. Estimated Weight in Patients Study Drugs (e.g. by inducing [40]. However, olanzapine-induced weight gain is also Estimated Weight sedation, changing metabolic rate, stimulating appetite Weight Change (kg): Change associated with low (kg) levels of activity [39], as the drug or inhibiting satiety, altering foodTest preferences, affecting Weight Change (kg): for Heterogeneity Random Effects at 10 Weeks: b has sedative actions [41], which may account for some of Fixed Effects Model in Fixed Effects Model Model Fixed Effects Model Drug or Study Condition a 2 Mean 95% CI df p Mean 95% observed CI Mean 95% gain. CI and Number of Studies the weight In addition, the drug can Behaviour Chlorpromazine (N=25; 13) 6.19 5.84 to 6.54 746.2 24 <0.0005 4.19 2.94 to 5.44 2.10 0.85 to 3.35 induce dry mouth due to, presumably, muscarinic antagClozapine (N=14; 12) 4.37 4.00 to 4.74 148.2 13 <0.0005 5.67 4.34 to 7.00 3.99 2.72 to 5.26 onism [38], 0.43 thus 0.65 enhanced Fluphenazine (N=11; 10) 0.95 0.73 to 1.17 142.0 10 <0.0005 1.13 0.09 to 2.17 to 1.51 intake of high calorie drinks Haloperidol (N=25; 19)Drugs can act 0.18 0.02 to 0.34 78.5 24 <0.0005 0.51 0.20 to 0.82 0.48 0.07 to 1.03 could also be involved. Furthermore, case studies have Control Loxapine (N=5; 3) 0.75 0.06 to 1.44 of intake 71.4 4 <0.0005 0.65 2.56 to 3.86 Molindone (N=17; 10) (directly 1.06 1.51 to 0.61 154.0and 16 <0.0005 0.10 1.39 to 1.19 that 0.81weight 2.16 togain 0.54 may also be due to reduced suggested (hypothalamic Nonpharmacologic control (N=7; 4) 0.79 0.46 to 1.12 21.0 6 0.002 0.82 0.08 to 1.56 1.33 0.84 to 1.82 mesolimbic). basal energy expenditure [42] (Similar effects of clozaOlanzapine (N=157; 7)or 1.53 1.49 to 1.57 4009.8 156 <0.0005 4.17 3.70 to 4.64 3.51 3.29 to 3.73 Perphenazine (N=4; 4)indirectly) 2.79 1.63 to 3.95 19.4 3 <0.0005 5.77 0.44 to 11.10 metabolic pine on resting rate have also been reported Pimozide (N=2; 2) 3.53 7.65 to 0.59 21.1 1 0.15 2.69 9.30 to 3.92 [43]). Weight gain is most Placebo (N=25; 22) at all these sites. 0.50 0.70 to 0.30 238.7 24 <0.0005 0.97 1.79 to 0.15 0.41 1.29 to 0.47 marked in patients with low Physiological and Polypharmacy (N=26; 13) 0.47 0.25 to 0.69 89.9 25 <0.0005 0.46 0.24 to 0.68 1.22 due 0.36 to 2.08 BMI [24,38,44], presumably to, the fact that systems endocrine effects. 2.61 2.07 to 3.14 28.8 7 <0.0005 2.49 1.51 to 3.47 Quetiapine (N=8; 3)d Risperidone (N=38; 26) 1.38 1.28 to 1.48 289.6 37 <0.0005 1.67 1.38 to 1.96 in inhibition 2.00 1.61 to 2.39 involved of weight gain (e.g. leptin producSertindole (N=7; 4) 2.94 2.70 to 3.18 6.2 6 0.39 2.94 2.70 to 3.18 2.92 1.76 to 4.08 tion) have not been recruited. Many studies have shown Fig.(N=16; 1 Interacting systems in antipsychotic Thioridazine/mesoridazine 12) 1.97 1.58possibly to 2.36 involved 129.1 15 <0.0005 2.81 1.59 to 4.03 3.49 1.75 to 5.23 Thiothixene (N=4; 3) drug-induced weight 2.31 gain. 1.45 to 3.17 5.2 3 0.16 2.89 1.01 to olanzapine-induced 4.77 that weight gain is associated with

Average clinical daily dose (micromoles per kilogram)

Dopamine D2 receptors

100 Promazine Clozapine Pipamperone 10

Serotonin 5HT2A/2C receptors Pipamperone Thioridazine Promazine Chlorpromazine

Thioridazine 10 Chlorpromazine

Fluanisone 1.0 Moperone

TGF-b/Smad3 signaling in obesity and diabetes CK Tan et al


1.0
4

Fluanisone Clozapine

Mediators+
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2.1 Antipsychotic drugs and weight gain incidence


#

Generally,antipsychotics is divided into first generation(typical),second generation(atypical),third generation and others.Among the antipsychotics drugs, the relative tendency to cause weight gain is as follows: clozapine > olazapine > risperidone= quetiapine > ziprasidone = aripiprazole
FIGURE 1. 95% Confidence IntervaIs for Weight Change After 10 Weeks on Standard Drug Doses, Estimated From a Random Effects Model
95% Confidence Interval for Weight Change (kg)

Trifluoperazine (N=2; 2) 0.34 0.86 to 1.54 0.1 1 0.75 0.34 0.86 to 1.54 Ziprasidone (N=25; 22) 0.64 0.40 to 0.88 69.2 24 <0.0005 0.28 0.27 to 0.83 0.04 0.49 to 0.57 a Some of the observations entering into the calculations are not independent (i.e., they may be from the same subjects measured at mulDiabetes, Obesity and Metabolism, 7, 2005, tiple points in480 time). This was not taken into account in calculation of the 478487 standard errors. The Ns shown are total number of means and number of independent cohorts the means came from. The number of means will always be greater than or equal to the number of independent means, because some cohorts may have been measured at multiple points in time. However, the number of independent means can exceed the number of trials, because some trials contained more than one independent cohort. For example, six trials provided data on ziprasidone, but because the data for men and women were provided separately and several different dose conditions were used with multiple groups, the six trials yield 22 independent cohorts. b Estimated from the fixed effects fitted regression (see text).

2004 Blackwell Publishing Ltd

Antipsychotics activated SMAD3, a downstream effector of the TGFb pathway, the TGF-b/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3-deficient mice are protected from diet-induced obesity.

Penfluridol Moperone result of decreased adipocyte number and size, suggesting adipocytes. Expansion of adipose tissue mass occurs through two cis-Thiothixene Trifluoperazine cis -Thiothixene distinct processes, namely hypertrophy (increase in cell size) and the presence of defective adipogenesis and lipid accumulation Penfluridol Droperidol Droperidol / Fluphenazine hyperplasia (increase in cell number). Adipocyte hypertrophy is in these mice. Gene expression proling of the Smad3 WAT (+)Butaclamol Trifluoperazine (+)Butaclamol Haloperidol Bromperidol achieved in mature adipocytes via an increase in lipid accumurevealed decreased expression Fluphenazine of PPARg2 transcripts, which Haloperidol Pimozide Bromperidol -Flupenthixol lation or 0.1 lipogenesis (i.e., triglyceride synthesis), which are coincided with expression of the preadipocyte0.1 an increased Trifluperidol Pimozide Clofluperol synergetic with aTrifluperidol decrease in lipolysis (i.e., triglyceride breakspecic marker preadipocyte factor-1.4 Lipid accumulation relies Benperidol Clofluperol Fluspirilene -Flupenthixol Spiroperidol down). In contrast, adipocyte hyperplasia relies on a complicated on the process of lipogenesis, which involves de novo synthesis of Benperidol Spiroperidol Fluspirilene process called adipogenesis that involves preadipocyte differenfatty acids (FAs) and glycerol, FA uptake and triglyceride synthesis. tiation. Among the 1.0 many transcriptional In fact, PPARg2 not only participates in adipocyte differentiation 10 100 1000 10 cascades controlling 100 1000 1.0 adipogenesis, peroxisome proliferator-activated receptor (PPAR)g2 and survival, but it also promotes lipid accumulation by activating is well characterized as the master regulator of the adipogenic target genes involved in lipogenesis, such as FA synthase, adipose 100 program.27 FA-binding 100 protein and phosphoenolpyruvate carboxykinase.31 Upon exposure to adipogenic hormones, such Histamine H1 receptors 1-Adrenergic receptors as glucocorticoids, cyclic AMP and insulin, the expression of Except for FA uptake, the expression of the rate-limiting enzymes Promazine transcription factors CCAAT/enhancer-binding protein (C/EBP)b involved in lipogenesis (e.g., FA synthase, acetyl-CoA carboxylase-1 Promazine Clozapine Clozapine and C/EBPd is transiently increased during adipocyte differentiaand stearoyl-CoA desaturase-1) and triglyceride synthesis Thioridazine Pipamperone Thioridazine tion. Together they induce PPAR g2 expression in Pipamperone the (e.g., diacylglycerol O-acyltransferase-1 and -2) was concomitantly / 10 10 Chlorpromazine preadipocytes, subsequently triggering full-blown adipocyte downregulated in the Smad3 WAT as evidence by decrease in Chlorpromazine 27 differentiation. PPARg2, a nuclear hormone receptor, heteroex vivo triglyceride synthesis.4 In contrast with the diminished Fluanisone Fluanisone dimerizes with the retinoid X receptor and induces the expression PPARg2 expression, a marked augmentation in the expression of C/EBPa, which subsequently takes over the function of C/EBPb level of PPARb/d and its regulated genes, such as uncoupling and C/EBP d in maintaining the transcription of PPARg2 via a protein (UCP )-2, UCP-3 and acyl-CoA oxidase (ACOX)-1, has also Moperone 1.0 1.0 Moperone positive feedback mechanism.27 Activated C/EBPa cooperates been found in the Smad3/ WAT.4 This is in agreement with the / Penfluridol cis -Thiothixene cis -Thiothixene Penfluridol with PPARg2 to induce the expression of other adipogenic genes nding that ex vivo FA b-oxidation was elevated in the Smad3 Droperidol Trifluoperazine Trifluoperazine 4 Droperidol involved in the differentiation program. WAT. The activation of PPARb/d in obese mice has been shown (+)Butaclamol Fluphenazine (+)Butaclamol Fluphenazine Previous in vitro studies showed that TGFb 1 inhibits adipogento selectively induce the expression of genes required for FA Haloperidol Bromperidol Haloperidol -Flupenthixol Bromperidol Pimozide esis independently of the Wnt/ b -catenin signaling pathway and b -oxidation and energy dissipation, such as UCP s and ACOX-1, butTrifluperidol -Flupenthixol 0.1 0.1 Clofluperol Pimozide Trifluperidol through the inhibitory effects of its downstream mediator Smad3 Fluspirilene not genes involved in lipogenesis and fat storage, which are Benperidol Benperidol Fluphenazine Clofluperol Spiroperidol on the transactivational potential of C/EBPs, thus abolishing the controlled by PPARg2.32 The underlying mechanism behind this Spiroperidol subsequent activation of PPARg2.6,28 Retinoic acid (RA) inhibits disparate effect of Smad3 on fat storage and burning involves the 100 1000 of Smad3 10 deciency on 100 1000 10,000 dual effects the PPARg2 and PPARb/d adipogenesis and its 1.0 action appears to10 block C/EBPb transcripKi drug This potency Ki drug potency promoters. Chromatin immunoprecipitation and re-chromatin tional potential early during differentiation. RA-mediated immunoprecipitation assays showed that C/EBPb was associated effect has also been found to be dependent on Smad3.29 A recent 166 Relationship between potencieswith of antipsychotic medications (asbp measured by therapeutic a specic C/EBP binding site at 494--485 upstream from nding also revealed an important role of clinical cellular RA-binding dose) and their for various Each shows clinical potency as a function the PPARgraph b/d promoter, thereby resulting in the recruitment to this of binding to protein-II in regulating the affinities transcriptional activity of RA receptors. through element of a transcriptional repressor complex containingcorrelates histone RA receptor. The early and sustained repression of cellular and D2 dopamine, 5HT serotonin, 1-adrenergic, H1 histamine receptors. Clinical potency with affin2A/2C 4 deacetylase 1 and the repression of PPARwere b/d. Besides, RA-binding by glucocorticoid receptor and C/EBPaand , C/EBPb can ity forprotein-II D2 dopamine receptors. In fact, dosing D2 dopamine receptor affinity not entirely independent of 30 respectively, is critical for adipogenesis. freely to bind to the PPARg2 promoter to exert and its adipogenic and However, recent in vivo doses each other, as receptor affinity is used to select test in clinical trials. Affinity receptor occupancy can / 4 lipogenic effects in normal WAT. and in vitro studies using Smad3 mice have demonstrated a In contrast, Smad3 deciency be judged in human subjects using positron emission tomography. (From Snyder SH. Drugs and the Brain. New York: paradoxical role of TGF-b/Smad3 as an activator of adipocyte leads to upregulation of an anti-adipogenic factor C/EBP Scientific 4,5 American Library; 1996.) differentiation. Primary mouse embryonic broblasts extracted homologous protein-10, which directly binds to C/EBPb to liberate PPARb/d transcription while impeding PPARg2 activation from Smad3/ mice display marked impairment in their ability to (Figure 2).4 This nding is further validated by the fact that C/EBP differentiate into white adipocytes and show reduced expression 5 of WAT-specic genes. This is consistent with the observations homologous protein-10 acts as a dominant-negative inhibitor of C/EBP by preventing its binding to DNA.33 that Smad3/ mice exhibit dramatic reduction in adiposity as a

Dietary+ changes+

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3. Conclusion
The correlation between Antipsychotic drugs and Obesity appeared to be linked to the neurobiology of individuals receptor levels, signaling pathways and genetic background. . The elucidation of these potential mechanisms could be important for quantification of patient risk during treatment with antipsychotics and can spur development of novel forms of treatment. Mechanisms of Antipsychotics drugs and onset of Obesity appears to be correlated but still rather disputable and further studies would need to be done to establish the links. It is widely accepted that drugs alone are insufficient to cause obesity. We should take into considerations of other factors such as socioeconomic, associated comorbidities such as hypertension, hypercholesterolemia, cardiovascular disease, and diabetes. Further researches are required to clarify the relationship between APDs mechanisms, signaling pathways and genetic polymorphisms.

r!

2.3 Effects on signaling pathway

4. References
Nature Publishing Group (2012) Metabolic Syndrome ePoster. [Online]. Available from: http://www.nature.com/nm/poster/index.html [Accessed 12th February 2013] Goulie, A.J., Cooper, G.D., Halford, J.C.G. (2005) Antipsychotic-induced weight gain. Diabetes, Obesity and Metabolism, 7(5), pp478-487. Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Cappelleri, J.C., Infante, M.C., Weiden, P.J. (1999) Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis. The American Journal of Psychiatry, 156(11), pp.1686-1696. Eric J. Nestler Steven E. Hyman Robert C. Malenka (2009) Molecular neuropharmacology.2nd ed. USA: The McGraw-Hill Companies. Tan, C.K., Chong, H.C., Tan, E.H.P., Tan, N.S. (2012) Getting Smad about obesity and diabetes. Nutrition and Diabetes 2012, 2(3), pp.1-13. Nemeroff, CB. (1997) Dosing the antipsychotic medication olanza-pine. Journal of Clinical Psychiatry 1997, 58(suppl10), pp4549. Umbricht, D.S., Pollack, S., Kane, J.M. (1994) Clozapine and weight gain Journal of Clinical Psychiatry 1994, 55 (suppl B), pp157160. Bernstein JG. (1987) Induction of obesity by psychotropic drugs. Annals of the New York Academy of Sciences 1987, 499, pp203215. Reynolds, G.P., Kirk, S.L. (2010) Metabolic side effects of Antipsychotics drug treatment- pharmacological mechanisms. Pharmacology & Therapeutics, 125(1), pp169-179. Roerig, J.L., Steffen, K.J., Mitchell J.E.(2011) Atypical antipsychotic-induced weight gain: insights into mechanisms of action. CNS drugs, 25(12), pp1035-1059.

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Placebo Conventional antipsychotics Novel antipsychotics Nonpharmacologic control

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Figure 2. TGF-b/Smad3 signaling promotes adipocyte differentiation but inhibits FA b-oxidation and thermogenesis.
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