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)

①  Nature Publishing Group (2012) Metabolic Syndrome ePoster. [Online]. Available from: http://www.nature.com/nm/poster/index.html [Accessed 12th February 2013]

②  Goulie, A.J., Cooper, G.D., Halford, J.C.G. (2005) Antipsychotic-induced weight gain. Diabetes, Obesity and Metabolism, 7(5), pp478-487. ③  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. ④  Eric J. Nestler Steven E. Hyman Robert C. Malenka (2009) Molecular neuropharmacology.2nd ed. USA: The McGraw-Hill Companies. ⑤  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. ⑥  Nemeroff, CB. (1997) Dosing the antipsychotic medication olanza-pine. Journal of Clinical Psychiatry 1997, 58(suppl10), pp45–49. ⑦  Umbricht, D.S., Pollack, S., Kane, J.M. (1994) Clozapine and weight gain Journal of Clinical Psychiatry 1994, 55 (suppl B), pp157–160. ⑧  Bernstein JG. (1987) Induction of obesity by psychotropic drugs. Annals of the New York Academy of Sciences 1987, 499, pp203–215. ⑨  Reynolds, G.P., Kirk, S.L. (2010) Metabolic side effects of Antipsychotics drug treatment- pharmacological mechanisms. Pharmacology &

Therapeutics, 125(1), pp169-179. ⑩  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.

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 β3 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.

1. Introduction

2. Discussion

2.1 Antipsychotic drugs and weight gain incidence

3. Conclusion

2.2 Receptors and neuropeptides interactions

4. References

2.4 Genetic polymorphisms

Weight gain can either be an increase in muscle mass, fat deposits or excess fluids such as water. Increase deposition of fats occur when energy intake and energy expenditure is imbalanced where energy intake is more than energy expenditure.

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.

The correlation between Antipsychotic drugs and Obesity appeared to be linked to the neurobiology of individual’s 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 APD’s mechanisms, signaling pathways and genetic polymorphisms.

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

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

although not perfect, concordance in these rank esti-

mates of weight gain liability with those outlined above.

In summary, in short-term studies there is a reason-

able consensus that novel APDs can probably be classi-

fied 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 mini-

mal weight gain (ziprasidone); and (iv) drugs for which

only limited data are available (zotepine and amisul-

pride), 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 aripi-

prazole (abilify) [33], which in very short-term studies

(4–6weeks) 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.

Mechanism(s) Involved in APD-induced Weight

Gain

Understanding such mechanism(s) requires that we map

the pharmacology of APDs, which, as described below

can be very complex, onto the many systems involved in

weight regulation. It is, therefore, perhaps unsurprising

that, to date, there is no consensus on the mechanism(s)

involved [21]. Weight gain occurs when energy expend-

iture is less than the energy intake. APDs can affect

these parameters in various ways (e.g. 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 inter-

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 mechan-

ism(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 formid-

able 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 short-

term treatment (vide supra), after 6 months treatment this

drug may be weight neutral [35,36], implying that toler-

ance may have developed to its weight-enhancing action.

Characterization of Weight Gain Induced by

Olanzapine

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)

[37], and many such studies are small scale ones. Olan-

zapine has been studied much more extensively than all

other APDs, due to the fact that it has been widely pre-

scribed and that it induces marked weight gain. Olanza-

pine-induced weight gain is associated with enhanced

appetite [24,38], increased food intake and adiposity [7].

Olanzapine-induced hyperphagia is observed in the

absence of any change in dietary composition [39].

Such effects of olanzapine have been suggested specula-

tively to be due to drug-induced binge-eating disorder

[40]. However, olanzapine-induced weight gain is also

associated with low levels of activity [39], as the drug

has sedative actions [41], which may account for some of

the observed weight gain. In addition, the drug can

induce dry mouth due to, presumably, muscarinic antag-

onism [38], thus enhanced intake of high calorie drinks

could also be involved. Furthermore, case studies have

suggested that weight gain may also be due to reduced

basal energy expenditure [42] (Similar effects of cloza-

pine on resting metabolic rate have also been reported

[43]). Weight gain is most marked in patients with low

BMI [24,38,44], due presumably to, the fact that systems

involved in inhibition of weight gain (e.g. leptin produc-

tion) have not been recruited. Many studies have shown

that olanzapine-induced weight gain is associated with

Drugs can act(directlyorindirectly)at all these sites.

Behaviour

Control of intake(hypothalamic andmesolimbic).

Physiological andendocrine effects.

Fig. 1 Interacting systems possibly involved in antipsychotic

drug-induced weight gain.

480 Diabetes, Obesity and Metabolism, 7, 2005, 478–487 # 2004 Blackwell Publishing Ltd

RA Antipsychotic-induced weight gain A. J. Goudie et al.

1690 Am J Psychiatry 156:11, November 1999

ANTIPSYCHOTIC-INDUCED WEIGHT GAIN

to induce clinically meaningful weight gain. Second,many authors report their weight gain data in an in-complete, idiosyncratic, and poorly defined manner.This is clearly an area that would benefit from guide-lines and standardization.

Table 4 displays the results from the quantitativemeta-analysis in detail. (Because of space limitations,studies used in the meta-analysis but not cited are not

listed in the reference list. A complete reference list canbe obtained from the first author.) The second columnin table 4 indicates the estimated mean weight changeacross all studies with the use of a fixed effects model(29) and the 95% confidence interval for that mean.These means, though interesting, are probably notmaximally informative, because the studies variedgreatly in terms of length of treatment and dosage.

TABLE 4. Estimated Weight Change in Patients Taking Study Drugs

Drug or Study Condition and Number of Studiesa

Weight Change (kg): Fixed Effects Model

Test for Heterogeneity in Fixed Effects Model

Weight Change (kg): Random Effects

Model

Estimated Weight Change (kg)at 10 Weeks:

Fixed Effects Modelb

Mean 95% CI χ2 df p Mean 95% CI Mean 95% CIChlorpromazine (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 3.35Clozapine (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 5.26Fluphenazine (N=11; 10) 0.95 0.73 to 1.17 142.0 10 <0.0005 1.13 0.09 to 2.17 0.43 –0.65 to 1.51Haloperidol (N=25; 19) 0.18 0.02 to 0.34 78.5 24 <0.0005 0.51 0.20 to 0.82 0.48 0.07 to 1.03Loxapine (N=5; 3) 0.75 0.06 to 1.44 71.4 4 <0.0005 0.65 –2.56 to 3.86 — —Molindone (N=17; 10) –1.06 –1.51 to –0.61 154.0 16 <0.0005 –0.10 –1.39 to 1.19 –0.81 –2.16 to 0.54Nonpharmacologic 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 1.82Olanzapine (N=157; 7) 1.53 1.49 to 1.57 4009.8 156 <0.0005 4.17 3.70 to 4.64 3.51 3.29 to 3.73Perphenazine (N=4; 4) 2.79 1.63 to 3.95 19.4 3 <0.0005 5.77 0.44 to 11.10 — —Pimozide (N=2; 2) –3.53 –7.65 to 0.59 21.1 1 0.15 –2.69 –9.30 to 3.92 — —Placebo (N=25; 22) –0.50 –0.70 to –0.30 238.7 24 <0.0005 –0.97 –1.79 to –0.15 –0.41 –1.29 to 0.47Polypharmacy (N=26; 13) 0.47 0.25 to 0.69 89.9 25 <0.0005 0.46 0.24 to 0.68 1.22 0.36 to 2.08Quetiapine (N=8; 3)d 2.61 2.07 to 3.14 28.8 7 <0.0005 2.49 1.51 to 3.47 — —Risperidone (N=38; 26) 1.38 1.28 to 1.48 289.6 37 <0.0005 1.67 1.38 to 1.96 2.00 1.61 to 2.39Sertindole (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 4.08Thioridazine/mesoridazine (N=16; 12) 1.97 1.58 to 2.36 129.1 15 <0.0005 2.81 1.59 to 4.03 3.49 1.75 to 5.23Thiothixene (N=4; 3) 2.31 1.45 to 3.17 5.2 3 0.16 2.89 1.01 to 4.77 — —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 0.57a Some of the observations entering into the calculations are not independent (i.e., they may be from the same subjects measured at mul-

tiple points in time). This was not taken into account in calculation of the standard errors. The Ns shown are total number of means andnumber of independent cohorts the means came from. The number of means will always be greater than or equal to the number of inde-pendent means, because some cohorts may have been measured at multiple points in time. However, the number of independent meanscan exceed the number of trials, because some trials contained more than one independent cohort. For example, six trials provided dataon ziprasidone, but because the data for men and women were provided separately and several different dose conditions were used withmultiple groups, the six trials yield 22 independent cohorts.

b Estimated from the fixed effects fitted regression (see text).

FIGURE 1. 95% Confidence IntervaIs for Weight Change After 10 Weeks on Standard Drug Doses, Estimated From a RandomEffects Model

Placebo

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400 Neuropharmacology of Neural Systems and DisordersPART 3

in dopamine release in the striatum and thereby to anincrease in dopamine breakdown products such as HVA.

Effects of antipsychotic drugs on D2 dopaminereceptors The dopamine hypothesis of antipsychoticdrug action was bolstered by studies of dopamine receptor

binding and function in rat striatum. Such studiesidentified two major dopamine binding sites, termedD1 and D2. Although some older antipsychotic drugs, suchas chlorpromazine, are potent antagonists of both recep-tor types, antagonism of the D2 receptor correlates withantipsychotic efficacy . Haloperidol, for example, a16–6

Relationship between clinical potencies of antipsychotic medications (as measured by therapeuticdose) and their affinities for various receptors. Each graph shows clinical potency as a function of binding toD2 dopamine, 5HT2A/2C serotonin, !1-adrenergic, and H1 histamine receptors. Clinical potency correlates with affin-ity for D2 dopamine receptors. In fact, dosing and D2 dopamine receptor affinity were not entirely independent ofeach other, as receptor affinity is used to select doses to test in clinical trials. Affinity and receptor occupancy canbe judged in human subjects using positron emission tomography. (From Snyder SH. Drugs and the Brain. New York:Scientific American Library; 1996.)

16–6

Dopamine D2 receptors Serotonin 5HT2A/2C receptors

!1-Adrenergic receptors Histamine H1 receptors

Promazine

PromazinePromazine

PromazineClozapine

ClozapineClozapine

Clozapine

Pipamperone

Pipamperone Pipamperone

Pipamperone

Penfluridol

Penfluridol Penfluridol

PenfluridolTrifluoperazine

Trifluoperazine Trifluoperazine

TrifluoperazineFluphenazine

Fluphenazine

Fluphenazine

Fluphenazine

FluphenazineHaloperidol

Haloperidol Haloperidol

HaloperidolPimozide

PimozidePimozide

PimozideClofluperol

Clofluperol

Clofluperol

ClofluperolFluspirilene

Fluspirilene

FluspirileneBenperidol

Ki drug potency

Benperidol Benperidol

Benperidol

Thioridazine

ThioridazineThioridazine

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Chlorpromazine Chlorpromazine

Chlorpromazine

Fluanisone

Fluanisone Fluanisone

Fluanisone

Moperone

MoperoneMoperone

Moperonecis-Thiothixene

cis-Thiothixene cis-Thiothixene

cis-ThiothixeneDroperidol

DroperidolDroperidol

Droperidol(+)Butaclamol

(+)Butaclamol(+)Butaclamol

(+)ButaclamolBromperidol

Bromperidol Bromperidol

Bromperidol

Trifluperidol

TrifluperidolTrifluperidol

Trifluperidol

Spiroperidol

Spiroperidol Spiroperidol

Spiroperidol

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!-Flupenthixol!-Flupenthixol

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The receptors of interest include serotonin 5-HT2A , 5-HT2C and 5-HT6 receptors , histamine H1 receptor, α1-α2- and β3 – adrenergic receptors , muscarinic M3 receptors and dopamine D1, D2, D3 receptors.

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.

2.3 Effects on signaling pathway

adipocytes. Expansion of adipose tissue mass occurs through twodistinct processes, namely hypertrophy (increase in cell size) andhyperplasia (increase in cell number). Adipocyte hypertrophy isachieved in mature adipocytes via an increase in lipid accumu-lation or lipogenesis (i.e., triglyceride synthesis), which aresynergetic with a decrease in lipolysis (i.e., triglyceride break-down). In contrast, adipocyte hyperplasia relies on a complicatedprocess called adipogenesis that involves preadipocyte differen-tiation. Among the many transcriptional cascades controllingadipogenesis, peroxisome proliferator-activated receptor (PPAR)g2is well characterized as the master regulator of the adipogenicprogram.27 Upon exposure to adipogenic hormones, suchas glucocorticoids, cyclic AMP and insulin, the expression oftranscription factors CCAAT/enhancer-binding protein (C/EBP)band C/EBPd is transiently increased during adipocyte differentia-tion. Together they induce PPARg2 expression in thepreadipocytes, subsequently triggering full-blown adipocytedifferentiation.27 PPARg2, a nuclear hormone receptor, hetero-dimerizes with the retinoid X receptor and induces the expressionof C/EBPa, which subsequently takes over the function of C/EBPband C/EBPd in maintaining the transcription of PPARg2 via apositive feedback mechanism.27 Activated C/EBPa cooperateswith PPARg2 to induce the expression of other adipogenic genesinvolved in the differentiation program.

Previous in vitro studies showed that TGF-b1 inhibits adipogen-esis independently of the Wnt/b-catenin signaling pathway andthrough the inhibitory effects of its downstream mediator Smad3on the transactivational potential of C/EBPs, thus abolishing thesubsequent activation of PPARg2.6,28 Retinoic acid (RA) inhibitsadipogenesis and its action appears to block C/EBPb transcrip-tional potential early during differentiation. This RA-mediatedeffect has also been found to be dependent on Smad3.29 A recentfinding also revealed an important role of cellular RA-bindingprotein-II in regulating the transcriptional activity of RA throughRA receptor. The early and sustained repression of cellularRA-binding protein-II by glucocorticoid receptor and C/EBPa,respectively, is critical for adipogenesis.30 However, recent in vivoand in vitro studies using Smad3!/! mice have demonstrated aparadoxical role of TGF-b/Smad3 as an activator of adipocytedifferentiation.4,5 Primary mouse embryonic fibroblasts extractedfrom Smad3!/! mice display marked impairment in their ability todifferentiate into white adipocytes and show reduced expressionof WAT-specific genes.5 This is consistent with the observationsthat Smad3!/! mice exhibit dramatic reduction in adiposity as a

result of decreased adipocyte number and size,4 suggestingthe presence of defective adipogenesis and lipid accumulationin these mice. Gene expression profiling of the Smad3!/! WATrevealed decreased expression of PPARg2 transcripts, whichcoincided with an increased expression of the preadipocyte-specific marker preadipocyte factor-1.4 Lipid accumulation relieson the process of lipogenesis, which involves de novo synthesis offatty acids (FAs) and glycerol, FA uptake and triglyceride synthesis.In fact, PPARg2 not only participates in adipocyte differentiationand survival, but it also promotes lipid accumulation by activatingtarget genes involved in lipogenesis, such as FA synthase, adiposeFA-binding protein and phosphoenolpyruvate carboxykinase.31

Except for FA uptake, the expression of the rate-limiting enzymesinvolved in lipogenesis (e.g., FA synthase, acetyl-CoA carboxylase-1and stearoyl-CoA desaturase-1) and triglyceride synthesis(e.g., diacylglycerol O-acyltransferase-1 and -2) was concomitantlydownregulated in the Smad3!/! WAT as evidence by decrease inex vivo triglyceride synthesis.4 In contrast with the diminishedPPARg2 expression, a marked augmentation in the expressionlevel of PPARb/d and its regulated genes, such as uncouplingprotein (UCP)-2, UCP-3 and acyl-CoA oxidase (ACOX)-1, has alsobeen found in the Smad3!/! WAT.4 This is in agreement with thefinding that ex vivo FA b-oxidation was elevated in the Smad3!/!

WAT.4 The activation of PPARb/d in obese mice has been shownto selectively induce the expression of genes required for FAb-oxidation and energy dissipation, such as UCPs and ACOX-1, butnot genes involved in lipogenesis and fat storage, which arecontrolled by PPARg2.32 The underlying mechanism behind thisdisparate effect of Smad3 on fat storage and burning involves thedual effects of Smad3 deficiency on the PPARg2 and PPARb/dpromoters. Chromatin immunoprecipitation and re-chromatinimmunoprecipitation assays showed that C/EBPb was associatedwith a specific C/EBP binding site at 494 -- 485 bp upstream fromthe PPARb/d promoter, thereby resulting in the recruitment to thiselement of a transcriptional repressor complex containing histonedeacetylase 1 and the repression of PPARb/d.4 Besides, C/EBPb canfreely bind to the PPARg2 promoter to exert its adipogenic andlipogenic effects in normal WAT.4 In contrast, Smad3 deficiencyleads to upregulation of an anti-adipogenic factor C/EBPhomologous protein-10, which directly binds to C/EBPb toliberate PPARb/d transcription while impeding PPARg2 activation(Figure 2).4 This finding is further validated by the fact that C/EBPhomologous protein-10 acts as a dominant-negative inhibitorof C/EBP by preventing its binding to DNA.33

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

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

3

Nutrition and Diabetes& 2012 Macmillan Publishers Limited

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.

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

Receptors Stimulation Inhibition Knockout model Remarks Serotonin 5HT2A 5HT2C 5HT6

↓Feeding,satiety ↓Feeding ↓Feeding

↑Feeding ↑Feeding ↓Feeding

Obese Resistance to dietary induced obesity

5HT2C antagonists (APD)attenuate reduction in food intake induced by leptin(leptin resistance)

Dopamine D1, D2, D3

↑Feeding

Obese -↓D2 receptor availability in brain

Histamine H1 (Clozapine, Olanzapine)

↑Feeding

Weight gain

H1 receptors on area of brains involved in energy homeostasis. ↑affinityà↑wt gain

Adrenergic α1, α2 β1/β2/β3

↑Feeding

Triple knockoutàobesity

α1-noradrenergic binding was inversely proportional to body weight gain

Muscarinic M3 (Olanzapine)

↑Feeding

↑feeding

↓ receptor occupancy with ↑ H1 receptor occupancy

Cannabinoid ↑Feeding Olanzapine decrease binding CB1receptors in brainstem

Peptide hormones Functions Remark

Orexigenic neuropeptide Y AGRP

↑Feeding

APDs activate hypothalamic orexin neurones (which stimulate food intake) to an extent correlated with their ability to induce weight gain .

Anorexigenic POMC

↓Feeding Clozapine has been reported to reduce the expression of the anorexigenic neuropeptide

Ghrelin ↑Food intake and adiposity Olanzepine cause secretion of ghrelin ,induce apeptite and weight gain.

Leptin ↓Weight Increased leptin or other hormones triggered by overfeeding produced inhibitory effect on feeding behaviour. Olanzapine cause decrease level of insulin and leptin, associate with weight gain.

Insulin ↓glucose level Insulin resistance is associated with physiological changes maintaining obesity. Insulin resistance caused by SGA result in leading to obesity

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An#$psycho#cs+induced+weight+change+

Baseline+ac#vity+

Baseline+Metabolism+

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

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pep#des+&+hormones+

regula#ng+appe#te+&+energy+

homeostasis+Dietary+changes+

Lifestyle+changes+

Baseline+an#$psycho#c+&+

comedica#ons+

Gene#c+effects+

Baseline+diet+

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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.