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Molecular Psychiatry (2004) 9, 1067–1074 & 2004 Nature Publishing Group All rights reserved 1359-4184/04 $30.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE A genome wide linkage study of obesity as secondary effect of in multigenerational families of eastern Quebec affected by psychoses YC Chagnon1,CMe´rette1, RH Bouchard1,CE´ mond1, M-A Roy1, M Maziade1 1Laval University Research Center Robert-Giffard, Beauport, Que´bec, Canada

Antipsychotics can induce in schizophrenic (SZ) and bipolar disorder (BP) patients serious body weight changes that increase risk for noncompliance to , and risk for cardiovascular diseases and diabetes. A genetic origin for this susceptibility to weight changes has been hypothesized because only a proportion of treated patients are affected, the degree of affection differing also in rates and magnitudes. In a first genome scan on obesity under antipsychotics in SZ and BP, we analyzed 21 multigenerational kindreds (508 family members) including several patients treated for a minimum of 3 years mainly with or chlopromazine. Obesity was defined from medical files and was shown to be 2.5 times more frequent in patients treated with antipsychotics than in untreated family members (30 vs 12%). The nine pedigrees that showed at least two occurrences of obesity under antipsychotics were submitted to model-based linkage analyses. We observed a suggestive linkage with a multipoint Lod score (MLS) of 2.74 at 12q24. This linkage finding vanished when we used as phenotypes, obesity unrelated to antipsychotics, and when we used SZ or BP. This suggests that this positive linkage result with obesity is specific to the use of antipsychotics. A potential candidate gene for this linkage is the pro-melanin-concentrating hormone (PMCH) gene located at less then 1 cM of the linkage. PMCH encodes a neuropeptide involved in the control of food intake, energy expenditure, and in anxiety/depression. This first genome scan targeting the obesity side effect of antipsychotics identified 12q24 as a susceptibility region. Molecular Psychiatry (2004) 9,1067–1074. doi:10.1038/sj.mp.4001537 Published online 29 June 2004 Keywords: ; bipolar disorder; melanin-concentrating hormone

Adverse metabolic effects of antipsychotics such as varies according to the used, the greatest weight gain may contribute to noncompliance with proportion being observed with and cloza- treatment and may lead to medical morbidity when pine, followed by and / obesity is reached.1 Indeed, obesity, as defined by a , and the lowest with and body mass index (BMI) of 30 kg/m2 and greater2 is , the latter even inducing a weight loss.5 associated with higher risks of developing cardiovas- Antipsychotics can also induce other metabolic pertur- cular diseases, hypertension, type II diabetes, dyslipi- bations such as hyperglycemia, insulin resistance and demia, arthritis, and some forms of cancer. The estimate diabetes, and dyslipidemia. For instance, we showed of the proportion of schizophrenic (SZ)- or bipolar that despite a similar body weight, olanzapine-treated disorder (BP)-treated patients experiencing significant SZ patients showed higher levels of plasma triglycer- weight gain for a given antipsychotic varies between 10 ides and very low-density lipoprotein cholesterol than and 50%, according to the population studied, and the -treated SZ.6 Moreover, we also observed dose and the duration of the follow-up. For example, that 32% of the olanzapine patients in contrast to 5% of 25% of the patients treated with experi- those on risperidone were characterized by the athero- enced significant weight gain after 1 month, and this genic metabolic triad.6 Hence, beyond the differences proportion reaches 50% in 1 year.3 In patients treated related to the drug used and the duration of follow-up, with olanzapine for up to 3 years, weight gain tended important interindividual differences exist in terms of toward a plateau at approximately 36 weeks.4 The the liability for weight gain and metabolic perturbations proportion of patients experiencing weight gain also under antipsychotic treatment. Indeed, even under the highly standardized treatment conditions of drug trials, only a proportion of subjects showed these side effects. Correspondence: Yvon Chagnon, Laval University Research Because of these interindividual differences, as well as Center Robert-Giffard, 2601 chemin de la Canardie`re, room the relatively high heritability of obesity,7 the suscept- F-6459, Beauport, Que´bec, Canada G1J 2B3. E-mail: [email protected] ibility to body weight change in psychotic patients as a Received 16 December 2003; revised 08 April 2004; accepted 06 side effect of antipsychotics has been hypothesized to May 2004 be of genetic origin. Genome scan of obesity under antipsychotics YC Chagnon et al 1068 Variations in genes related to the neurotransmitter To investigate this possible genomic hypothesis of systems affected by antipsychotics are prime candi- the occurrence of obesity in patients treated with dates to explain the interindividual differences in antipsychotics, we took advantage of 21 already weight gain in psychotic patients, following exposure collected multigenerational families presenting multi- to antipsychotics. These neurotransmitter systems ple incidences of SZ and BP and on which we include the serotonergic, , alpha adre- reported a genome scan.21 We use these genotypes to nergic, muscarinic, histaminergic, and cholinergic redo the linkage analysis on a phenotype of obesity neurotransmitter systems8,9 for which antipsychotics under antipsychotics (ObA) among nine of these show various profiles of affinity.10 The serotonergic pedigrees showing at least two ObA occurrences. system has been the main target of candidate gene We hypothesized that the obesity side effect observed studies of antipsychotic-induced weight gain and in a subgroup of antipsychotic-treated patients is

metabolic perturbations. receptor 5-HT2C is expressed only when an appropriate combination of located in human chromosome Xq24, and it was different genetic variants is present. Different genetic

reported in knockout mice for 5-HT2C, a leptin- variant combinations would be responsible for the independent hyperphagia resulting in obesity and variations in magnitude, rate, and kinetics of obesity type II diabetes.11 Associations have also been in a given environment. A suggestive linkage on 12 reported in humans between 5-HT2C and BMI, chromosome 12 has been detected. 13 between 5-HT2A and energy intake in obese subjects, and between 5-HT1B and minimum lifetime BMI in women with bulimia nervosa,14 whereas no associa- Material and methods

tion was observed with the 5-HT2C Cys23Ser poly- Subjects morphism and body weight gain.15 Reynolds et al16 A total of 21 multigenerational kindred affected by SZ analyzed the 5-HT2C À759C/T polymorphism in first- or BP, including 508 family members, were ascer- episode patients treated with chlorpromazine or tained and diagnosed using a lifetime best estimate risperidone, and those carrying the À759T variant consensus (DSM-III-R) procedure. The ascertainment showed an antipsychotic-induced weight gain 3 times and Ethics Committee approval have already been lower. reported.21,22 All patients received various antipsy- The possible role of genes involved in the metabo- chotics for at least 3 years. The history of antipsycho- lism of antipsychotics has also been studied. For tic medication was drawn from the lifetime medical instance, cytochrome P450 CYP2D6 enzyme metabo- records of the subjects.23 The mean age of onset was lizes many drugs including antipsychotics, with its 25.4 (78.5) years for SZ and 28.8 (710.3) years for BP, activity ranging from complete deficiency to ultrafast and the mean current age was 43.8 and 56.4 years, metabolism depending on at least 16 different known respectively. The medical and nursing notes from all alleles.17 A significant genotype effect of a CYP2D6 medical records, in- and out-patients across life, were polymorphism on percent change of BMI in 11 reviewed. A phenotype of ObA was diagnosed, blind patients under olanzapine has been reported.18 to genotypes, when clear written notes about obesity Basile et al19 have tested nine candidate genes, from psychiatrists or nurses were recorded (N ¼ 39). including the cytochrome P450 1A2 in 80 DSM-IV Patients for whom a light excess of weight or a healthy SZ patients prospectively assessed for - weight was clearly noted were rated as non-ObA induced weight gain. No significant difference in (N ¼ 89). Those having no indication of corpulence weight gain was observed between genotypes of the status were classified as unknown and were not used different polymorphisms using covariance analysis, in the linkage analyses. In order to assess the but some trends were observed for 5-HT2C, the b3 and specificity of the linkage results to antipsychotic a1a-adrenergic receptors, and the tumor necrosis effect on obesity, linkage analyses were also per- factor alpha (TNFa).19 Finally, Reynolds20 reported a formed using an obesity (Ob) phenotype that included lower weight gain under chlorpromazine or risper- all ObA cases and Ob present in family members, who idone in SZ patients carrying the G allele were not taking antipsychotics. Linkage results with of the 2548A/G polymorphism in the promoter of ObA were also contrasted with those obtained with the leptin gene indicating that a gene involved in the SZ and BP phenotypes themselves (see Mazaide appetite and fat mass regulation could also be et al24 for definitions) allowing to distinguish ObA associated with the side effect of antipsychotics on linkages from linkages related to liability to SZ or BP. body weight. These prior studies on the genetics of antipsycho- Genotyping tic-induced weight gain and metabolic perturbations Our genome scan on the SZ/BP cohort21,22 included relied on a candidate gene approach. Given limited a 470 microsatellite markers with a mean spacing of 6.5 priori knowledge on the pathophysiology of these centimorgan (cM), according to the Genetic Location side effects, linkage studies offer a significant advan- DataBase (LDB) maps (http://cedar.genetics.soton.a- tage, since they do not depend on such a priori c.uk/). For genotyping, we used radioactive tagging of information. To our knowledge, no such linkage study PCR products and visual genotyping,21,22,oran of obesity in antipsychotic-treated psychotic patients automated genotyping procedure (SAGA; LiCor) has yet been reported. based on laser infrared automatic DNA sequencers

Molecular Psychiatry Genome scan of obesity under antipsychotics YC Chagnon et al 1069 Table 1 Penetrance parameter valuesa used in linkage antipsychotics prescribed, the two most frequently analysis used were haloperidol taken alone (23%) or combined with another antipsychotic (7%), and chlorpromazine dd Dd DD Disease gene (13 and 8%, respectively). The rate of methotrime- frequency prazine was 12% (4% alone, 8% combined with other antipsychotics), fluphenazine 9%, and thioridazine Dominant 8%. Finally, and risperidone, the latter models DOM1 0.0037 0.7 0.7 0.01 being the only , each have a 7% DOM2 0.0001 1.0 1.0 0.01 rate. Other antipsychotics were prescribed at a frequency of less than 2%. Five patients received Recessive different combinations of three drugs at the same time models (see footnote of Table 2). Some 44% of the patients REC1 0.0008 0.0008 0.7 0.10 who previously received a different antipsychotic REC2 0.0001 0.0001 1.0 0.10 were currently on haloperidol, 22% were on chlor- , and 10% on fluphenazine. On the other aThe penetrance values refer to the probability of having a hand, some 21% of patients had also received given affection status conditional to the age class and to lithium, and 6% various . One patient each of the three possible genotypes at the disease locus, received . that is, dd, Dd, and DD where the allele D identifies the Table 3 shows the distribution of the subjects susceptibility allele (for unaffected subjects, the linkage according to their obesity status. Among the 128 program will use one of these values). patients treated with antipsychotics, 30% (39/128) developed obesity compared to 12% (18/150) in untreated relatives. Table 3 suggests that obesity (LiCor)25, where genotypes were confirmed visually. tended to show familial aggregation in our sample. Mendelian inheritance of genotypes was checked For example, seven out of nine patients under including all family members (PedCheck software26), antipsychotics became obese in family 230, whereas and accuracy of the genotyping was evaluated by six patients out of eight treated with antipsychotics adding blind duplicates to the DNA samples. remained at an acceptable weight in pedigree 105A (Table 3). Nine out of our 21 pedigrees (Table 3) had at Linkage analysis least two occurrences of ObA phenotype, and were Only pedigrees with at least two occurrences of ObA used in a model-based genome-wide linkage analysis. could be included in the analysis. Model-based We detected a suggestive linkage at a genome-wide linkage analyses were used since growing evidence scale level30,31 on chromosome 12q24 with a multi- shows that they are more powerful than model-free or point Lod score (MLS) of 2.74, involving markers nonparametric analyses27,28 even when the mode of D12S79 and D12S366. The flanking marker located at inheritance specified is only approximately correct, 1.5 cM centromeric to the linked region showed a provided that at least one dominant and one recessive consistent yet lower MLS of 1.72. No linkage signals model are considered.29 We considered both a were obtained with the Ob, SZ, or BP phenotypes at complete and a reduced penetrance model for each this locus (Table 4). Promising evidence of linkage dominant and recessive transmission (Table 1). The (Lod scores greater then 1.2) were also observed at analyses were first carried out using both affected and 1p36 (Lod ¼ 1.62), 6p21 (Lod ¼ 1.72), 8q12 unaffected (AU) patients, and then using affected- (Lod ¼ 1.93), 9q34 (Lod ¼ 1.71), 15q26 (Lod ¼ 1.43), only (AO) to reduce the impact of a mis-specification and 16q24 (Lod ¼ 1.37) (Table 4). However, some of in the penetrance parameter. When analyzing the the linkage signals with ObA in these regions were ObA phenotype, (i) ObA patients were classified as also detected (Lod41.2) with Ob, for example, at affected, (ii) the non-ObA as unaffected, and (iii) the 1p36 and 6p21, or with SZ or BP at 6p21 and 15q26, Ob or non-Ob family-related subjects without anti- with most linkages going down in multipoint analysis psychotic as unknown (Table 2). The linkage signals (Table 4). were classified as being either suggestive (Lod scores between 2.5 and 3.9) according to Lander and Discussion Kruglyak thresholds30 adjusted for multiple testing,31 or promising (Lod scores greater than 1.2) according The chromosomal region 12q24 showed the strongest to Rao and Province.32 No significant Lod score linkage results with obesity in patients taking anti- (43.9)30,31 was observed with ObA in this study in psychotics (Table 4; Figure 1), which suggests that a contrast with those previously reported in this sample locus for ObA is located within this region. Moreover, with SZ and BP phenotypes.22 no linkage signal was observed with the obesity alone phenotype or with SZ or BP, which suggests a Results specificity of this linkage to the ObA phenotype. The current results must be interpreted taking into Table 2 shows the antipsychotics used by the patients account the following methodological issues and included in the linkage study. Among the 13 different limitations. First, we assessed the power of

Molecular Psychiatry oeua Psychiatry Molecular 1070

Table 2 Percentages of antipsychotics, lithium, and antidepressants taken by the patients included in the linkage study eoesa foeiyudrantipsychotics under obesity of scan Genome

Antipsychotics Halo- Chlor- Metho- Fluphe- Thiori- Perphe- Risperi- Pipo- Thiopro- Loxa- Trifluo- Prome- Chlorpro- Total peridol promazine trimeprazine nazine dazine nazine done tiazine pal perazine thazine thixene

Haloperidol 23.4 12.7 4.2 7.0 4.2 2.8 2.8 1.4 2.8 5.6 43.7 Chlorpromazine 2.6 13.0 1.4 2.8 2.8 4.2 4.2 1.4 4.2 1.4 22.5 Methotrimeprazine 3.9 2.8 1.4 1.4 5.6 Fluphenazine 9.1 2.8 1.4 1.4 1.4 1.4 1.4 9.9 Chagnon YC Thioridazine 2.6 3.9 3.9 1.4 1.4 1.4 1.4 5.6 Perphenazine 2.6 1.3 1.3 5.2 1.4 1.4

Risperidone 1.3 3.9 1.4 2.8 4.2 al et 3.9 1.4 1.4 1.3 0.0 1.3 2.6 1.3 2.8 2.8 Loxapal 1.3 0 1.3 1.3 1.3 2.6 1.3 0 1.3 0 0 1.3 0 0

Total 29.9 20.8 11.7 9.1 7.8 6.5 6.5 3.9 1.3 1.3 1.3 100.0 Lithium 9.1 1.3 2.6 3.9 2.6 19.5 1.3 1.3 2.6 5.2

The diagonal reports the percentage of those receiving only one antipsychotic, and below the diagonal, the percentages of those receiving two antipsychotics. Above the diagonal, the percentages of those having previously taken other antipsychotics are indicated. For example, 43.7% of patients using haloperidol have also taken previously other antipsychotics. The number of patients having taken three drugs are the following: chlorpromazine–thioproperazine–methotrimeprazine: 1; chlorpromazine–thioproperazine– perphenazine: 1; haloperidol–chlorpromazine–thioproperazine: 1; haloperidol–chlorpromazine–methotrimeprazine: 1; thioridazine––perphenazine: 1; haloperidol–chlorpromazine–lithium: 2; haloperidol–trifluoperazine–lithium: 1. Genome scan of obesity under antipsychotics YC Chagnon et al 1071 Table 3 Number of subjects in each multigenerational (#Gen) pedigree affected by schizophrenia or bipolar disorder, and by obesity

Pedigree #Gen Antipsychotics No-antipsychotics

ObA Non-ObA Total Ob Non-Ob Total

101 4 4 9 13 4 3 7 103 5 3 5 8 1 2 3 210 5 3 7 10 2 27 29 230 4 7 2 9 0 1 1 255 5 5 7 12 0 11 11 105A 4 2 6 8 1 4 5 125 4 3 5 8 1 3 4 211A 3 2 2 4 0 5 5 220 4 2 4 6 3 20 23 Total Scan 31 47 78 12 76 88 Other 3–5 8 42 50 6 56 62

Total 39 89 128 18 132 150

ObA: obese under antipsychotic; Ob: obese without antipsychotic.

Table 4 Genome scan results for obesity under antipsychotics (ObA), obesity unrelated to antipsychotics (Ob), schizophrenia (SZ), and bipolar disorder (BP)

Region Marker Location Modelsa ObA Ob SZ/BP b c,d (cM) Zmax (y) MLS Zmax (y) Disease Zmax (y)

1p36 D1S552 22.58 DOM2 1.32 (0.15) 1.62 1.05 (0.20) BP 0.27 (0.15) 6p21 D6S260 29.93 DOM2 1.70 (0.15) 0.76 1.62 (0.25) SZ 1.68 (0.10) 8q12 D8S1136 68.67 DOM2 1.59 (0.15) 1.93 0.02 (0.40) BP 0.43 (0.25) 9q34 D9S282 131.28 DOM1 1.71 (0.10) 0.32 0 (0.45) BP 0.81 (0.15) 12q24 D12S2070 121.95 DOM2 1.72 (0.15) — — — — D12S79 123.42 DOM2 2.10 (0.15) 2.74 0.49 (0.35) BP 0.67 (0.20) D12S366 128.87 DOM2 1.72 (0.20) — — — — 15q26 D15S657 104.61 DOM2 1.43 (0.20) 1.21 0.38 (0.35) BP 2.31 (0.05) 16q24 D16S516 92.62 REC2 1.37 (0.15) 0.92 0.41 (0.30) BP 0.83 (0.15) aThe models refer to those described in Table 1. Note that all these results were obtained using an affected–unaffected definition. b Zmax is the two-point lod score. cMLS is the multipoint lod score. dSuggestive result (2.5rLodr3.9)[30,31] is indicated in bold in contrast to promising results (LodZ1.2)[32]. parametric analyses in the nine families under study develop the ObA phenotype while taking antipsycho- by simulations with SLINK and MSIM.33 The ELOD tics. This may be related to the fact that the psychotic was 3.8 and the power to observe a Lod score over 2.5 patients included had to receive antipsychotics for at (suggestive linkage) and 3.9 (significant linkage) was least 3 years, which provided enough time for ObA to 74 and 44%, respectively. In these simulations, we develop completely. observed one suggestive Lod score of 2.74 and no Third, it is also possible that some patients were significant linkage. Given the expected power of this obese before beginning antipsychotics. Then, it can be subsample, even if this result did not reach our argued that our linkage signal at 12q24 could be stringent threshold for significance, this result can be related to general obesity rather than to treatment- considered as a fairly clear evidence of linkage. related obesity. However, our linkage analysis, in- Second, we obtained weaker linkage evidence cluding all obese patients and related family mem- using the affected-only phenotype (data not shown) bers, did not yield linkage evidence in this than using affected/nonaffected analyses. This sug- chromosomal region, which supports the specificity gests that few antipsychotic-treated patients were of this linkage signal to treatement-related obesity. nonpenetrant for the ObA phenotype, that is, there Fourth, our phenotype definition of obesity, were few carriers of the gene variations who did not although made blind and based on the extensive

Molecular Psychiatry Genome scan of obesity under antipsychotics YC Chagnon et al 1072

Figure 1 Linkage results at 12q24 with surrounding genes, ESTs and markers according to genetic (G) or physical (P) maps. PMCH: pro-melanin-concentrating hormone; SCA2: spinocerebrellar ataxia 2; NIDDM2: non-insulin-dependent mellitus 2; M: megabase; MLS: multipoint Lod score.

contemporary lifetime information from all medical to the drug used. Our patients were treated with a records, is nevertheless less optimal than direct variety of antipsychotics (mainly haloperidol or concurrent measures. In fact, the analyzed cohort chlorpromazine), which is unavoidable in linkage was not initially designed to study a phenotype of studies in which the standardization of drug treat- obesity, and this phenotype was developed from the ment is very difficult. Additionally, a significant written notes from psychiatrists and nurses in the number of patients had previously received antipsy- medical records of the psychotic patients. This is a chotics other than those currently used (Table 2). potential limitation of the study. To estimate the Thus, the linkage signal that we observed may be reliability on misclassification rate for ObA, we related to a common liability to weight gain under gathered a direct measurement of BMI in 21 patients chlorpromazine or haloperidol. However, additionnal included in the current study. We observed a loci may also be involved in mediating side effects of misclassification rate of around 10% since two other antipsychotics. patients were misclassified as non-ObA while show- According to the LDB genetic map, the linked ing a BMI greater than 30 kg/m2. However, such region on chromosome 12q24 (Figure 1) is located at potential errors in measure would have generated less than 1 cM from the pro-melanin-concentrating type 2 (false negative) rather than type 1 (false hormone (PMCH) gene, encoding in rodents a known positive) errors in linkage. Indeed, previous work by orexigenic neuropeptide. On the other hand, accord- Martinez et al34 has shown that phenotypic misclas- ing to the physical map from the Human Genome sification leads to ‘yan overestimation of the recom- Sequence project (NCBI) the linked region becomes bination fraction and a loss of power of the linkage closer (0.05 megabases) to a cluster of genes including test’. This statement applies both to false positive (ie, the cerebrellar ataxia 2 (SCA2) and the non-insulin- non-ObA subjects erroneously classified ObA) and dependant diabetes mellitus II (NIDDM2) loci than to false negative (ie, ObA subjects erroneously classified the PMCH locus (16 megabases). Also, two expressed non-ObA) phenotypic assignments. transcript sequences (HS.240246 and HS.131598) Fifth, the genes involved in the genetic control of with no known protein similarity are located very the side effects of antipsychotics may vary according close to our linkage with ObA (Figure 1). However,

Molecular Psychiatry Genome scan of obesity under antipsychotics YC Chagnon et al 1073 our strongest linked marker D12S79 showed two –308G/A single nucleotide polymorphism located in locations on the physical map, which casts doubts on the promoter region of TNFa and weight changes its real physical location. PMCH should be retained as following 6 weeks of clozapine medication.19 How- a strong candidate for ObA in this region because of ever, this study could suffer from a lack of power its very close location to our linked marker according since only three out of 74 patients were found as to the LDB genetic map. Since the LDB map has been homozygote A/A, where twice the amount of body used for locating the markers in linkage analysis, this weight change was shown in contrast to A/G and G/G map should be more representative of the location of genotypes (P ¼ 0.15). Also, patients were treated for a the linked markers. Moreover, numerous observations relatively short period of time (6 weeks) in contrast, support PMCH as the candidate gene for antipsycho- for example, to our study, where patients received tic-induced obesity. For instance, PMCH is over- antipsychotics for at least 3 years, thus allowing expressed in the hypothalamus of ob/ob mice complete penetrance of the obesity phenotype. lacking the leptin gene;35 fasting, increasing its In conclusion, our results supported the hypothesis expression. When injected in the lateral ventricles that the obesity observed in the SZ or BP patients of rats, food consumption increased indicating an treated with antipsychotics could be genetic in origin, orexigenic effect.35 Mice deficient in MCH (PMCH and that the chromosomal region 12q24 includes a knockout mice) have reduced body weight and gene that may be involved. They also raise the leanness due to both hypophagia and an inappropri- hypothesis that variations in genes directly involved ately increased metabolic rate. Inversely, transgenic in body composition, such as, possibly PMCH, in mice overexpressing MCH become obese and insulin contrast with those being known targets of antipsy- resistant.36 Additionally, PMCH knockout mice chotics, such as the serotonin receptors, could also be showed a reduced amount of leptin and pro-opiome- involved in the side effects of antipsychotics on body lanocortin mRNA,37 which indicates that MCH works weight in psychotic patients. downstream to the leptin and melanocortin systems. Two MCH receptors (MCHR1, MCHR2) are known in humans, and MCHR1-deficient mice have normal Acknowledgements body weight but, surprisingly, are hyperphagic, their We acknowledge Louise Be´langer, Vincent Lamothe, leanness being a consequence of hyperactivity and of 38 and Julie Lemay for their review of the patient files an altered metabolism. Moreover, it has been allowing the definition of obesity phenotypes. This reported that the synaptosomal associated protein work was partially supported by IRSC GR-14501. SNAP-7941, a specific antagonist of MCHR1, not only inhibited food intake stimulated by a central admin- istration of MCH in rats, but also produced effects References similar to clinically used antidepressants and anxio- lytics in three animal models of depression/anxiety.39 1 Stanton JM. Weight gain associated with neuroleptic medication: a Hence, the MCH pathway is involved in both body review. Schizophr Bull 1995; 21: 463–472. 2 National Heart, Lung, and Blood Institute. Obesity Education weight and mood status regulations, and it remains to Initiative: Clinical Guidelines on the Identification, Evaluation, be shown how antipsychotics may influence these and Treatment of Overweight and Obesity in Adults. US Depart- regulations. ment of Health and Human Services, 1998. Other linkages, even being weak and showing some 3 Falloon I, Watt DC, Shepherd M. A comparative controlled trial of pimozide and fluphenazine decanoate in the continuation therapy divergences according to the 2-point and MLS results, of schizophrenia. Psychol Med 1978; 8: 59–70. or showing some linkages with either Ob, SZ, or BP, 4 Jones B, Basson BR, Walker DJ, Crawford AM, Kinon BJ. Weight are close to other possible candidate genes for obesity change and atypical antipsychotic treatment in patients with antipsychotic side effects. These included two known schizophrenia. 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Res Publ this family of receptors, is associated with antipsy- Assoc Res Nerv Ment Dis 1991; 69: 205–218. chotic effects on body weight.40 The clinical implica- 8 Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye tions of CHRM5 is actually unknown. However, the NC et al. Radioreceptor binding profile of the atypical antipsycho- muscarinic receptors are known to bind antipsycho- tic olanzapine. Neuropsychopharmacology 1996; 14: 87–96. 41 9 Richelson E, Souder T. Binding of antipsychotic drugs to human tics, and mice lacking the muscarinic receptor 3 are brain receptors focus on newer generation compounds. Life Sci 42 hypophagic and lean, whereas the blockade of the 2000; 68: 29–39. cortical muscarinic receptor inhibited the memory of 10 Wetterling T. Bodyweight gain with atypical antipsychotics. A taste.43 Finally, TNFa is activated by psychotropic comparative review. 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