One- half of US adults are cur rently over weight (body

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1 Antipsychotic Metabolic Effects: Weight Gain, Diabetes Mellitus, and Lipid Abnormalities Roger S McIn tyre, MD, FRCPC 1, Sonia M McCann, BSc, BSc 2, Sid ney H Ken nedy, MD, FRCPC 3 Ob jec tive: To re view pub lished and non pub lished lit era ture de scrib ing changes in weight, glu cose ho meo sta sis, and lipid mi lieu with an tipsy chot ics. Meth ods: A Med line search was com pleted us ing the words weight gain, dia be tes mel li tus, cho les terol, tri glyc erides, risperi - done, clo zap ine, ol an zap ine, queti apine, zi pra si done, pre dic tors, pro lac tin, obe sity, and con ven tional an tipsy chot ics. Pub li ca - tions, in clud ing origi nal ar ti cles, re view ar ti cles, let ters to the edi tor, ab stracts or post ers pre sented at pro fes sional meet ings in the last 4 years, and ref er ences from pub lished ar ti cles, were col lected. Manu fac tur ers, in clud ing Eli Lilly Can ada Inc, Janssen- Ortho Inc, Pfizer Can ada Inc, As tra Zeneca Inc, and No var tis Phar ma ceu ti cals, were con tacted to re trieve ad di tional medi cal in for ma tion. Re sults: The topic of antipsychotic- induced weight gain is un der stud ied, and there are rela tively few well- controlled studies. Weight gain as a side ef fect has been de scribed with both con ven tional and atypi cal an tipsy chot ics. Moreo ver, some atypi cal an - tipsy chot ics are as so ci ated with de novo dia be tes mel li tus and in creased se rum tri glyc eride lev els. Pre dic tors of weight gain may be age, base line body mass in dex, ap pe tite stimu la tion, pre vi ous an tipsy chotic ex po sure, and an tipsy chotic treat ment du ra tion. Con clu sion: Sig nifi cant weight gain is re ported with the ex ist ing atypi cal an tipsy chot ics. The weight gain de scribed is highly dis - tress ing to pa tients, may re duce treat ment ad her ence, and may in crease the rela tive risk for dia be tes mel li tus and hy per tri glyc - eride mia. Phy si cians em ploy ing these agents should rou tinely moni tor weight, fast ing blood glu cose, and lipid pro files. (Can J Psy chia try 2001;46: ) Key Words: weight gain, obesity, obe sity comor bid ity, dia be tes mel li tus, tri glyc eride, atypical an tipsy chot ics, con ven tional an tipsy chot ics One- half of US adults are cur rently over weight (body mass in dex [BMI] 25 kg/m 2 ) while 22 % are obese (BMI 30 kg/m 2 ) (1 3). (Weight clas si fi ca tion by BMI is shown in Ta ble 1.) These preva lence sta tis tics re flect a rapid tra jec tory of change over the past 20 years (4). Obe sity in - creases the risk for a myr iad of medi cal dis or ders, some forms of can cer, and all- cause mor tal ity (1,5). Re ports of weight gain in duced by con ven tional an tipsy chot - ics (CAPs, for ex am ple, chlor pro maz ine) be gan to ap pear soon af ter their avail abil ity (6,7). Atypi cal an tipsy chot ics (AAs, for ex am ple, risperi done, ol an zap ine, queti apine, clo - zap ine) of fer en hanced ef fi cacy in the treatment of psy chotic dis or ders and are rec om mended as a first- line phar ma co - thera peu tic strat egy for schizo phre nia (8). Al though AAs of - fer an im proved neu ro logi cal side- effect pro file, sev eral AAs ap pear to pos sess greater weight gain li abil ity than CAPs. Antipsychotic- induced weight gain has been de scribed as highly dis tress ing to pa tients, ad versely af fect ing selfesteem, and, al though dif fi cult to quan tify, de creas ing treat - ment ad her ence (9). The es ti mated prevalence of obe sity among per sons with schizo phre nia con verges with and may exceed that of the gen eral popu la tion (10). Fur ther, chronic psy chi at ric pa tients ex hibit high rela tive rates of ad verse health be hav iours (such as smok ing) and sev eral medi cal dis or ders (11). Manuscript received December 1999, revised, and accepted January Staff Psychiatrist, Cen tre for Addiction and Mental Health, Toronto; Assis - tant Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario. 2 Formerly, Clinical Research Co-ordinator, Centre for Addiction and Men tal Health, Toronto, Ontario. 3 Clinical Director, Mood and Anxi ety Program, Centre for Addiction and Mental Health, Toronto; Professor, Department of Psychiatry, University of Toronto, Toronto, Ontario. Address for correspondence: Dr RS McIntyre, Centre for Addiction and Mental Health, Clarke Site, Mood and Anxi ety Disorders Program, 250 Col - lege Street, Toronto, ON M5T 1R8 roger_mcintyre@camh.net This re view sum ma rizes AA- induced weight gain and the po - ten tial im pact of these agents on the glu cose ho meo static net - work and lipid mi lieu. Weight Gain: Comparative Liability Antipsychotic- induced weight gain is often re ported in an idio syn chra tic man ner. Most authors re port an ab so lute weight change; less re ported, but per haps more clinically rele vant, are meas ure ments such as weight gain greater than or equal to 7% from base line or pe riph eral ver sus cen tral Can J Psychiatry, Vol 46, April

2 274 The Canadian Journal of Psychiatry Vol 46, No 3 Table 1. Weight classification by Body Mass Index (BMI) NHLBI a terminology BMI (kg/m 2 ) range WHO b clas si fi ca tion Underweight < 18.5 Un der weight Normal Nor mal range Overweight Preobese Obesity class Obese class 1 Obesity class Obese class 2 Obesity class Obese class 3 a Na tional Heart, Lung, and Blood In sti tute (1); b World Health Or gani za tion (2) adi pos ity. A sum mary of many studies is shown in Ta ble 2. Doss (12) ret ro spec tively de scribed dif fer en tial weight gain li abil ity in 78 ran domly as signed pa tients af ter 36 weeks of CAP treat ment. CAP- induced weight gain is com pa ra ble with oral and de pot for mu la tions (13,14). Clo zap ine has clearly es tab lished weight gain li abil ity (15 18). Hum mer and oth ers (19) pro spec tively fol lowed 81 am bu la tory pa tients with re frac tory psy chotic dis or ders. Af - ter 1 year, 36% of pa tients had gained more than 10% of their ini tial body weight. The av er age weight gain for all clozapine- treated pa tients was 3.5 kg. Al li son and oth ers (20) metaana lyzed 81 treat ment trials (18 in cluded pla cebo com pari son) at least 10 weeks in du ra tion, com par ing mean weight gain among pa tients using CAPs and AAs ap proved for use or un der in ves ti ga tion. Mean weight gain with sev eral atypi cal agents was greater than that with con ven tion als. In ter est ingly, the AA mo lin done was as so ci - ated with a 0.39 kg re duc tion. Mo lin done s weight loss and ano rexi ant prop er ties have been de scribed pre vi ously (21 23). Wirshing and oth ers (24) ret ro spec tively as sessed weight gain in 92 male pa tients with schizo phre nia en rolled in 8 an - tipsy chotic ef fi cacy studies con ducted over 6 years. Ol an zap - ine and clo zap ine im parted the most weight gain, risperi done was in ter me di ate, and sert in dole in duced less weight gain than ha loperi dol. The authors de ter mined that weight gain pla teaued at 20 weeks with ol an zap ine and clo zap ine ver sus 10 weeks with risperi done and sert in dole. An in verse relation be tween base line BMI and weight gain was not seen. These weight gain data con verge with re sults from short- term, par - al lel group- design studies in schizo phre nia and bi po lar disor - der (25 28). The dis pa rate phar ma col ogy of these agents may be stow dif fer en tial weight gain li abil ity (20,29). In sum mary, CAPs and AAs exhibit dif fer en tial weight gain li abil ity. Clo zap ine ap pears to have the greatest weight gain po ten tial, zi pra si done the least (20,29). The ex tent of weight gain de scribed with these agents may in crease the risk for weight- related medi cal comor bid ity (5). Clinical Correlates The find ings of sev eral stud ies are sum ma rized in Table 3. Younger pa tients may be at higher risk of weight gain (30). The rela tive risk of sex re mains to be elu ci dated be cause re - sults are con tra dic tory (31,32). Ki non and oth ers (31) evalu - ated dis pa rate clini cal vari ables for their abil ity to cor re late weight gain with ol an zap ine use. Cor re lates reaching sig nifi - cance are listed in Ta ble 3. Weight gain cor re lat ing with psy cho pa thologi cal im prove - ment has been de scribed since the pre neu ro lep tic era (33), with chlor pro maz ine (34), and more re cently with clo zap ine (16). The ef fects of clo zap ine re quire further elu ci da tion be - cause other in ves ti ga tors have ob tained vari able re sults (15,17,18). Wet ter ling and Mu brig brodt (35) ret ro spec tively as sessed weight gain in 91 pa tients with pri mary psy chotic dis or ders re ceiv ing AAs. They con cluded that weight gain was sig nifi - cantly greater in pa tients re ceiv ing AAs (when com pared with CAPs), in pa tients with a base line nor mal weight (BMI kg/m 2 ), in younger pa tients, and in per sons not pre vi ously treated with an tipsy chot ics. The weight gain tra jec tory was de scribed ear lier by Wirshing and oth ers (24). Further data are pre sented in Ta ble 3 for clo - zap ine, ol an zap ine, and risperi done (36 38; data on file at Eli Lilly). There ex ists an equivo cal re la tion be tween du ra tion of treat ment with AAs and weight gain (13,14,31,39). Com bin ing AAs with other weight gain- inducing psy cho - tropic agents ap pears to impart an additive weight gain ef fect (28). Lith ium and an ti con vul sants have well- documented weight gain po ten tial (40), and val proic acid has been as so ci - ated with in su lin re sis tance, ele vated leptin and in su lin lev els (41), and changes in the re pro duc tive hor mone mi lieu in some pa tients (42). Mechanisms of Weight Gain Obe sity and weight gain are the re sult of a com plex conflu - ence of en vi ron mental, be hav ioural, ge netic, and neu ro - chemi cal fac tors. AAs ex hibit pleio tropic re cep tor af fin ity (43). Many, but not all, pa tients ex pe ri enc ing weight gain with an tipsy chotic drugs re port in creased ap pe tite, binge eat - ing, car bo hy drate crav ing, food pref er ence changes, and de - creased satiety. Do pa mine or nora drena line an tago nism at the lat eral hypo - thala mus may af fect sa ti ety (44 47). In creas ing the avail - abil ity of se ro tonin or ac ti vat ing se ro tonin re cep tors re duces food con sump tion, while blocking se ro tonin re cep tors in - creases food in take.the se ro tonin re cep tor sub type(s) re - spon si ble for stimu lat ing food intake re main a mat ter of specu la tion. Cur rently, the 5-HT 2C re cep tor is un der ac tive in ves ti ga tion (48).

3 April 2001 Antipsychotic Metabolic Effects: Weight Gain, Diabetes Mellitus, and Lipid Abnormalities 275 Table 2. Comparative weight gain liability Study Sample Method Treatment Duration Findings Doss (12) 78 schizophrenia Retrospective 5 antipsychotics 36 weeks Mean weight increases from baseline Thiothixene 6 kg, a fluphenazine 4 kg, haloperidol 3 kg, a thioridazine 1.5 kg, loxapine 4.1 kg Johnson and Breen (13) 132 schizophrenia Depot fluphenazine deconoate versus flupenthixol deconoate Ganguli (14) 125 schizophrenia Depot haloperidol or fluphenazine Hummer and others (19) 81 refractory psychotic s Clozapine Clozapine (n = 31) versus haloperidol (n = 11) 24 weeks 28% gained more than 3 kg, 7% gained more than 7 kg 46% gained > 2% baseline weight 26% gained > 5% baseline weight 11% gained > 10% baseline weight No statistical difference between fluphenazine and flupenthixol Not reported by authors 42% males obese (BMI > 28 kg/m 2 ) 49% females obese (BMI > 27 kg/m 2 ) 52 weeks 35.7% gained > 10% baseline weight within first 12 weeks of clozapine treatment. Clozapine (mean 3.5 kg) > haloperidol (mean 1.5 kg) Allison and others (20) Not reported by authors Metaanalysis 81 trials of conventional antipsychotics and atypical antipsychotics 10 weeks Mean weight increases from baseline Clozapine 4.45 kg, olanzapine 4.15 kg, risperidone 2.10 kg, haloperidol 1.08 kg, ziprasidone 0.04 kg, molindone 0.39 kg, placebo 0.74 kg Wirshing and others (24) 92 male schizophrenia Retrospective 5 antipsychotics: weight gain and trajectory Tran and others (25) Conley and others (26) 339 schizophrenia, schizophreniform or schizoaffective 407 schizophrenia and schizoaffective Guille and others (28) 43 bipolar I, schizoaffective bipolar Csernansky and others (38) a Sta tis ti cally significant 365 schizophrenic and schizoaffective double-blind double-blind Risperidone (mean modal dose 7.2 mg) versus olanzapine (mean modal dose 17.2 mg) Flexible dose risperidone versus olanzapine Risperidone versus olanzapine versus clozapine Risperidone versus haloperidol 6 years Olanzapine, clozapine > risperidone > haloperidol > sertindole 28 weeks Olanzapine significantly > efficacy; risperidone in negative symptoms Olanzapine 4.1 (SD 5.9 kg) Risperidone 2.3 (SD 4.8 kg) 8 weeks Both significant efficacy but risperidone > olanzapine for positive and mood or anxiety symptoms of positive and negative syndrome scale Weight gain: olanzapine 3.9 kg > risperidone 2.0 kg 12 weeks Comparable efficacy for all treatments Weight gain: olanzapine 10.6 kg, risperidone 1.7 kg, clozapine sample size too small 2 years Risperidone 2.3 kg > haloperidol 0.74 kg Te cott and oth ers (49) bred a strain of mice, ge neti cally de fi - cient in 5-HT 2C re cep tors, that be came obese and had a propensity for sei zures. Fen flu ramine and m- chlorophenylpiperazine (m-cpp), both 5-HT 2C ago nists, have been shown to sup press ap pe tite and de crease food in - take in hu mans (50 52). Fur ther, the 5-HT 2A/C re cep tor is an - tago nized to vary ing de grees with the ex ist ing AAs (43,53,54). An ti his ta mines and low- potency an tipsy chot ics have welldocumented ef fects on weight gain. His ta mine an tago nism stimu lates ap pe tite (55). Wirshing (24) noted an ex po nen tial re la tion be tween antipsychotic- induced weight gain and histamine-1 re cep tor (H 1 ) af fin ity. Clo zap ine ex hib its his ta - mine blockade af fin ity more than 20- fold greater than risperi - done (43). It has been hy pothe sized that pro lac tin ele va tion may stimu - late feed ing cen tres in the brain by chang ing the es tro gen tes - tos ter one ra tio (56), which in turn modi fies the func tion ing of satiety- related neu rons in the ven tral me dial and para ven - tricu lar hy po thala mus (57,58). Fur ther, in vi tro ex peri ments have dem on strated adi po cyte in su lin in sen si tiv ity in hy per - pro lac ti ne mic con di tions (59). How ever, evi dence militating against pro lac tin ele va tion as a suf fi cient mecha nis tic vari able is the ab sence of sus tained pro lac tin ele va tion with clo zap ine and ol an zap ine (60). Sev eral pep tides have been im pli cated in the control of appe - tite, in clud ing leptin (3). Leptin is a prod uct of the obese gene found in sev eral tis sues. Leptin, re leased by adi po cytes, is be - lieved to act at the level of the hy po thala mus, modu lat ing ap - pe tite, en ergy ex pen di ture, and the neu ro en do crine axis. It has been re ported that se rum leptin con cen tra tions cor re late posi tively with BMI and per cent age of body fat (61,62). Se vere obe sity has been re ported in sub jects con geni tally de - fi cient in leptin and in ani mals with de fec tive leptin re cep tors (63). The ad mini stra tion of leptin in both clini cal and preclinical sam ples is vari ously re ported to re duce obe sity (61,64 66). In flu ences on leptin lev els by clo zap ine, ol an zap ine, ha - loperi dol, and val proic acid have been re ported (41,67,68) (Ta ble 4). Al though leptin in creases may be a prod uct of weight gain, its etio patho genic con tri bu tion and in flu ence on symp tom change re main far from clear and are un der cur rent in ves ti ga tion. Col lec tively, data from several re search para digms con verge and sug gest that AA- induced weight gain or obe sity is mecha nis ti cally re lated to an as- yet- undetermined in ter play

4 276 The Canadian Journal of Psychiatry Vol 46, No 3 Table 3. Clinical correlates of weight gain liability Demographic Findings Study Age Younger more at risk Kelly and others (28), Kinon and others (31), Wetterling and others (35) Sex Females > males Males > females Gopalaswamy and Morgan (32) Kinon and others (31) Baseline Weights Baseline normal weight at higher risk Kinon and others (31) Previous Treatment Exposure Naive at higher risk Wetterling and others (35) Duration Clinical Response Risperidone weight gain 3.3 kg after 1 year Risperidone (mean modal dose daily 4.9 mg) weight gain 2.3 kg after 2 years Olanzapine (mean 15, SD 2.5 mg daily) weight gain 11.8 kg after 1 year Olanzapine weight gain tapers between weeks 30 & 40 Clozapine weight gain greatest during 1st year but continues up to 36 months and then plateaus Plateaued at 20 weeks with olanzapine and clozapine versus 10 weeks with risperidone Positive relation No relation Amery and others (36) Csernansky and others (38) Beasley and others (37) Eli Lilly and Company (unpublished observations) Umbricht and others (17) Wirshing and others (24) Leadbetter and others (16), Kinon and others (31), Krypsin-Exner (33), Planansky and Heilizer (34) Lamberti and others (15), Umbricht and others (17), Bustillo and others (18) Antipsychotic Class Atypical > conventionals Wetterling and others (35), Allison and others (20) Study Treatment Table 4. Leptin levels and weight gain Number of subjects Duration Findings Brömel and others (67) Clozapine weeks Increased mean body weight, BMI, mean fat mass, and mean lean body mass a Increased serum leptin level (53.6% over baseline) Verrotti and others (41) Valproic acid 40 (females, epilepsy) Kraus and others (68) Clozapine versus olanzapine versus haloperidol versus no treatment BMI = Body Mass In dex. a Sta tis ti cally sig nifi cant (P < ) 52 weeks 15 obese patients showed higher serum leptin and insulin levels than patients who did not gain weight 44 4 weeks Clozapine and olanzapine showed increased weight, BMI, and leptin levels Haloperidol and control had no change in leptin levels of mul ti ple neu ro trans mit ter and re cep tor in ter ac tions, with re sul tant changes in ap pe tite, en ergy in take, and feed ing be - hav iour. Novel re search para digms re fin ing pu ta tive mecha - nis tic links be tween AAs and neu ro pep tides are un der way. Treatment The 1998 Na tional In sti tute of Health Evi dence Re port and other stud ies con firm how dif fi cult it is for peo ple to lose weight (69,70). Given the dif fi cul ties ex pe ri enced by many cog ni tively sound in di vidu als in im ple ment ing dietary and be hav ioural in ter ven tions, it is un der stand able that those with psy chi at ric dis or ders rep re sent a unique chal lenge. A suc - cess ful weight man age ment pro gram must in clude ex er cise, a bal anced diet, and be hav ioural modi fi ca tion (70). In ter est - ingly, Wirshing de ter mined that weight gain with ol an zap ine and risperi done, un like clo zap ine, was ame na ble to ex er cise and nu tri tional coun sel ling (24). Phar ma cologi cal strate gies em ploy ing com pounds with weight loss prop er ties as an ti dotes to antipsychotic- induced weight gain have been pre vi ously de scribed (51). Their util ity in psy chi at ric pa tients is com pli cated by their phar ma co dy - namic and phar ma coki netic pro file. These agents recruit and en gage monoamines im pli cated in the pa tho physi ol ogy of mood and psy chotic dis or ders. Their use in schizo phre nia is gen er ally dis cour aged, given the dearth of sys tem atic ef fi - cacy and safety data (71,72). Orlistat and sibu tra mine are cur - rently FDA- approved weight loss agents in the US (73). Orlis tat is an ex vivo agent with mini mal sys temic absorption that blocks pan cre atic and gas tric li pases. Sibu tra mine, an ano rexi ant, is a se ro tonin and nora dren er gic re up take blocker, with po ten tial va so pres sor ac tiv ity. Nei ther has been sys tem ati cally stud ied for antipsychotic- induced weight gain. Topi ra mate is a sulfamate- substituted fruc tose de riva tive syn the sized in 1980 and a novel an tie pi lep tic agent (74). In open stud ies and chart re views, topi ra mate has dem on strated broad spec trum thy mo lep tic ef fects in some bi po lar dis or der pa tients (75 82). Con trolled tri als in acute mania are un der - way. One ad verse event of topi ra mate is loss of ap pe tite and weight. McIntyre and oth ers (83) de scribed their ex pe ri ence com par ing the ef fi cacy and safety of bupropion slow re lease (SR) (mean dose 250 mg) and topi ra mate (mean dose 180 mg) when added to mood stabilizer ther apy for 8 weeks in 36 per - sons with bi po lar de pres sion. Both agents ex hib ited com pa ra - ble an ti de pres sant ef fi cacy, with more pa tients los ing weight with topi ra mate (mean = 5.8 kg vs 1.8 kg for bupropion SR; P < 0.01). Weight loss was re ported in sev eral other topi ra - mate studies (76,77,79 82).

5 April 2001 Antipsychotic Metabolic Effects: Weight Gain, Diabetes Mellitus, and Lipid Abnormalities 277 Report Age, Sex, Race Diagnosis Table 5. Antipsychotic-related glucose intolerance Diabetes history Family history Diabetes Obesity history Weight gain during treatment Findings Kamran and others (86) Clozapine 41, M, B Schizophrenia No NR NR NR Hyperglycemia Koval and others (87) Clozapine 34, F, B Schizophrenia No Type I NR NR Hyperglycemia Kostakoglu and others (88) Clozapine 42, M, NR Schizophrenia No Type II Yes NR Hyperglycemia Koren and others (89) Clozapine 37, M, W Schizophrenia No No NR NR Hyperglycemia Peterson and Byrd (90) Clozapine 46, M, B Schizophrenia No Type NR NR NR Dia betic ke toa ci do sis Popli and others (91) Clozapine 32, M, B Schizophrenia No Type I/II Yes Yes de novo dia be tes mel li tus Clozapine 44, M, B Schizoaffective No No Yes Yes de novo dia be tes mel li tus Clozapine 51, M, W Schizophrenia Type II NR NR No Exacerbation dia be tes mel li tus Clozapine 51, M, B Schizophrenia Type II NR NR No Exacerbation dia be tes mel li tus Wirshing and others (92) Clozapine 47, M, B Schizophrenia Glucose intolerance Clozapine 32, M, B Schizoaffective No Yes Yes de novo dia be tes mel li tus No No No Yes de novo dia be tes mel li tus Clozapine 43, M, B Schizophrenia No Type II Yes Yes de novo dia be tes mel li tus Clozapine 41, M, B Not reported No No Yes No de novo dia be tes mel li tus Olanzapine 38, M, B Schizophrenia No No Yes Yes de novo dia be tes mel li tus Olanzapine 56, M, W Schizophrenia No No Yes No de novo dia be tes mel li tus Sobel and others (95) Quetiapine 42, M, W Bipolar No No NR NR de novo dia be tes mel li tus Goldstein and others (93) Olanzapine 42, F, W Schizoaffective No Type II No Yes Dia betic ke toa ci do sis, de novo dia be tes mel li tus Olanzapine 40, F, W Schizophrenia No No Yes Yes Dia betic ke toa ci do sis, de novo dia be tes mel li tus Olanzapine 41, F, W Bipolar No No Yes NR de novo dia be tes mel li tus Olanzapine 47, M,W Schizoaffective No Type II Yes Yes de novo dia be tes mel li tus Olanzapine 43, M,W Bipolar No No Yes Yes de novo dia be tes mel li tus Olanzapine 39, M, W Schizoaffective Glucose intolerance Type II Yes No, lost de novo dia be tes mel li tus Olanzapine 38, M, W Schizophrenia No Remote Yes No de novo dia be tes mel li tus Lindenmayer and others (94) Olanzapine 50, M, B Schizophrenia No NR Yes Initial, then lost Dia betic ke toa ci do sis, de novo dia be tes mel li tus B = black; F = female; M = male; NR = not re ported by author; Type I = insulin- dependent dia be tes; Type II = non insulin de pend ent dia be tes; W = white Other weight- management strate gies in clude switching from an agent with high to low weight gain li abil ity. Re in stein and oth ers (84) de scribed weight re duc tion and im proved gly ce - mic con trol with clo zap ine dose re duc tion and queti apine aug men ta tion. In sum mary, sec on dary pre ven ta tive ef forts such as diet and ex er cise are of ten poorly ad hered to by in di vidu als with out psy chi at ric dis or ders. Ef fec tive weight- management pro - grams for psy chi at ric pa tients need to con sider pri mary pre - ven tion; that is, proper diet and ex er cise coun sel ling and be hav ioural modi fi ca tion from the be gin ning of treat ment. Un for tu nately, there is no pub lished re search on at tempts to sys tem ati cally man age AA weight gain. Glucose Homeostasis Stud ies de scrib ing the ef fects of an tipsy chotic agents on glu - cose me tabo lism are sum ma rized in Table 5. Weight gain is a ro bust risk fac tor for type II dia be tes mel li tus (DM) (84). Ninety per cent of di ag nos able DM is type II and 90% of type II DM in di vidu als are obese (85). Case re ports of hy per gly ce mia, dia betic ke toa ci do sis (DKA), and de novo DM have been de scribed with clo zap ine (86 91). Wirshing and oth ers de scribed 6 pa tients, 4 re ceiv ing clo zap ine and 2 ol an zap ine, who de vel oped de novo DM (92). Gold stein and oth ers ex tended these find ings (93). They de - scribed 7 cases of olanzapine- induced hy per gly ce mia (2 of which pre sented with DKA). Pa tients de vel oped de novo DM be tween 5 weeks and 17 months (mean 26 weeks) after treat - ment ini tia tion. One- half of their sam ple had known family his to ries of type II DM, and 4 pa tients ex pe ri enced weight gain while tak ing ol an zap ine. Other case re ports with olan - zap ine and queti apine have been reported (94 97). Zoler (98) de scribed a pos si ble as so cia tion be tween an tipsy - chotic ex po sure and type II DM in pa tients with schizo phre - nia. By chart re view, he ret ro spec tively as sessed 396 pa tients. Dif fer en tial in ci dence of type II DM was re ported with clo - zap ine, ol an zap ine, ha loperi dol, risperi done, and fluphe - nazine (Fig ure 1). This cross- sectional data, how ever, does not con firm cau sa tion.

6 278 The Canadian Journal of Psychiatry Vol 46, No 3 Table 6. Hypertriglyceridemia Study Treatment Mean dose Number of subjects Duration Serum Triglyceride Findings Vampini and others (106) Clozapine 400 mg daily 1 15 months Increased levels Ghaeli and Dufresne (107) Clozapine versus CAPs (not reported) 1109, SD 397 mg daily 626, SD 817 mg daily 67 (37 males, 30 females) Gaulin and others (108) Clozapine Not reported 177 (129 males, 48 females) Haloperidol Not reported 45 (35 males, 10 females) Dursun and others (109) Clozapine 352 mg daily 8 (2 males, 6 females) Osser and others (110) Olanzapine 13.8, SD 4.4 mg daily 25 (21 males, 4 females) Sheitman and others (111) Olanzapine 19 mg daily 9 (7 males, 2 females) a Sta tis ti cally dif fer ent P < 0.001; b Sta tis ti cally dif fer ent P < 0.01 Antipsychotic for min 1 year Males 88 weeks Females 75 weeks Males 59 weeks Females85 weeks Clozapine increased (mean 2.99, SD 1.81 mmol/l) a CAPs increased (mean 1.68, SD 0.88 mmol/l) Increased in males (mean 1.06, SD 1.87 mmol/l) b Increased in females (mean 0.66, SD 1.28 mmol/l) Decreased in males (mean 0.39, SD 1.93 mmol/l) Increased in females (mean 0.92, SD 1.29 mmol/l) 12 weeks Increased (11%) but no significant changes in plasma cholesterol levels 12 weeks Increased (mean 0.68 mmol/l) 16 months Increased (mean 0.79 mmol/l) 5/9 50% increase in level Mean weight gain 10 kg Differential Incidence of Type II DM Clozapine Olanzapine Haloperdol Risperidone Fluephenazine Melk ers son and oth ers (104) re ported on 28 pa tients re ceiv ing CAPs and 13 receiving clo zap ine. Out come meas ures in cluded body weight, se rum con cen tra tion of an - tipsy chotic agents, glu cose, in su lin, insulin- like growth fac tor 1, and insulinlike growth fac tor binding pro tein 1. Pa - tients re ceiv ing clo zap ine had ele vated in - su lin lev els when com pared with in di vidu als re ceiv ing CAPs. Fur ther, there was a posi tive cor re la tion be tween se rum con cen tra tions of clo zap ine and in su lin lev - els (not seen with CAPs). The authors hy - pothe size that clo zap ine may re sult in in su lin re sis tance lead ing to sub se quent sec on dary hyper in su line mia. *Lifetime age-adjusted DM prevalence in general population 5-7% (85) Figure 1. Antipsychotic-associated Type II diabetes mellitus; Zoler (98) It has not been es tab lished to date that an tipsy chot ics in duce DM. It is not known if these agents ex ac er bate pre- existing subthresh old DM or dis rupt a nor mal glu cose ho meo static sys tem. All of the cur rently avail able AAs in duce weight gain. Being over weight of ten pres ages overt type II DM. Weight gain may be the first step in a cas cade of events lead - ing to in su lin re sis tance, glu cose in tol er ance, and DM. Weight gain, how ever, may be one of sev eral ave nues for antipsychotic- related glu cose dys regu la tion. Weight in crease is re ported in most, but not all, cases. Se ro tonin and its recep - tors are known to af fect glu cose ho meo sta sis in a com plex, con tra dic tory way. Hy per gly ce mia with AAs may be due to block ade of 5-HT 1A re cep tors on pan cre atic beta cells (99). This pathway may ex plain pan crea ti tis re ported with clozap - ine treatment ( ). Demo graphic risk fac tors for antipsychotic- induced DM have been de - scribed. Four teen of the 15 pub lished case re ports by Wirshing and oth ers (92) in - volved men, and 11 of the 14 cases in which eth nic ity was re - ported in volved peo ple of Af ri can de scent. It is known that Abo rigi nals, His pan ics and those of Asian or Af ri can de scent are at greater risk of de vel op ing DM (85). Moreo ver, many of the re ported cases had posi tive per sonal or fam ily his to ries for DM (87 91,93). The evi dence sug gests, but does not con firm, that for pa tients with (or with out) risk fac tors for DM, some AAs may pre dis - pose and por tend li abil ity to overt DM (105). The 1998 Cana - dian Clini cal Prac tice Guide lines for the Man age ment of Dia be tes rec om mend meas ur ing the fasting plasma glu cose (FPG) levels every 1 to 3 years of those with risk fac tors for DM, such as obe sity, a low level of high- density lipoprotein (HDL) cho les terol ( 0.9 mmol/l), or an ele vated fasting level of tri glyc erides (> 2.8 mmol/l) (85).

7 April 2001 Antipsychotic Metabolic Effects: Weight Gain, Diabetes Mellitus, and Lipid Abnormalities 279 Atypical Antipsychotics and Hypertriglyceridemia The as so cia tion be tween treat ment with AAs and hy per tri - glyc eride mia found in vari ous studies is sum ma rized in Ta ble 6. Clo zap ine is as so ci ated with ab nor mal tri glyc eride lev els ( ). Osser and oth ers evalu ated the ef fects of ol an zap - ine on weight, fast ing total cho les terol, and tri glyc erides in 25 pa tients with schizo phre nia and re lated psy cho sis (110). Af - ter 12 weeks of ol an zap ine treat ment, the group mean body weight in creased 5.4 kg (P < 0.02). Al though there was no sig nifi cant change in cho les terol lev els, the mean tri glyc eride lev els rose by 37%. Lith ium treatment and con comi tant in - creases in body weight cor re lated with in creases in tri glyc - eride lev els. Sheit man and oth ers (111) de scribed the ef fect of ad junc tive ol an zap ine on lipid pa rame ters in 9 chroni cally in sti tu tion al - ized pa tients with schizo phre nia. Base line weight and lipid pan els were meas ured. No change was noted in cho les terol pro file. Pa tients had a mean weight gain of 10 kg. The authors rec om mended rou tine lipid moni tor ing in pa tients receiving ol an zap ine, par ticu larly if DM risk fac tors are pres ent. The im por tance of AAs being cor re lated with hy per tri gly - cide mia is high lighted by uni vari ate analysis, which cor re - lates ele vated se rum tri glyc eride lev els with in creased risk for coro nary ar tery dis ease (93). In light of those data, it is recom - mended that lipid pro files be rou tinely moni tored in pa tients re ceiv ing AAs. Con clu sion Ex cess weight and obe sity are as so ci ated with sig nifi cant mor bid ity and mor tal ity. Some AAs have greater weight gain li abil ity than the CAPs. Antipsychotic- induced weight gain ad versely af fects well- being and may con trib ute to non com - pli ance, which in creases re cur rence risk. Weight gain of ten pres ages overt dia be tes mel li tus and hy per tri gly cide mia. On the whole, pa tients with schizo phre nia have high preva - lence of over weight and re lated medi cal dis or ders when com - pared with in di vidu als in the gen eral popu la tion. Sev eral pre ven ta tive strate gies have been enu mer ated, in clud ing diet, ex er cise, and be hav ioural modi fi ca tion, and per haps the cau - tious use of ad junc tive agents with weight loss properties. These vari ous strate gies have not here to fore been sys tem ati - cally evalu ated. The dif fi culty in di vidu als have in losing weight and the very sig nifi cant dele te ri ous ef fects of weight gain on over all health high light the need for pri mary pre ven tion. The ex ist ing lit era ture de scrib ing antipsychotic- induced weight gain is in the ag gre gate poorly con trolled and of ten re - ported idio syn crati cally. For ex am ple, es ti mates of weight gain af ter short-term and long-term treat ment should be clari - fied, cate gori cal in creases in weight gain (such as a 7% gain from baseline) are often help ful, and pe riph eral ver sus cen tral Clinical Im pli ca tions Weight gain liability with several atypical antipsychotics (AAs) is greater than with conventional antipsychotics (CAPs). The weight gain reported with several AAs impacts negatively on patient well-being and overall general health. Clinicians should routinely monitor weight, fasting blood glu cose, and lipid profile in patients receiving AAs. Limi ta tions Available data are largely descriptive, and there are few wellcontrolled studies. Little research exists to guide physicians on how to effectively pre - vent, monitor, and treat antipsychotic-induced weight gain. adi pos ity es ti mates may confer dif fer en tial mor bid ity risk. It is not pos si ble to know the ex tent of the prob lem of glu cose and lipid ir regu lari ties, be cause there are rela tively few re - ports against a back ground of mil lions of pre scrip tions and pa tient years of ex po sure. Fur ther, ba sic prin ci ples of meas - ure ment, such as speci fy ing whether as says were fast ing or ran dom, are rarely em ployed. Sys tem atic re search with more rig our is cur rently un der way. Cli ni cians should in cor po rate in for ma tion on the meta bolic ef fects of an tipsy chotic agents into their treatment- selection pro cess and psycho edu ca tion for pa tients. Phy si cians are en cour aged to monitor weight, plasma glu cose, and lipid pa rame ters in pa tients receiving these agents. References 1. 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9 April 2001 Antipsychotic Metabolic Effects: Weight Gain, Diabetes Mellitus, and Lipid Abnormalities Shank RP, Gar docki JF, Vaught JL, Davis CB, Schup sky JJ, Raffa RB, and others. Topi ra mate: pre clini cal evaluation of a struc tur ally novel an ti con vul sant. Epi lep sia 1994;35: Mar cotte D. Use of topi ra mate, a new anti- leptic as a mood sta bi lizer. J Af fect Dis - ord 1998;50: Cal brese JR, Keck PE Jr, McElroy SL, Werkner JE. Topi ra mate in severe treatment- refractory ma nia. Poster pre sented at the An nual Meeting of the Ameri - can Psy chi at ric As so cia tion; 1998 Jun; To ronto, ON. 77. McEl roy SL, Kmetz GF, Keck PE Jr. A pilot of ad junc tive topi ra mate in the treat - ment of bi po lar dis or der. Poster pre sented at 21st Con gress of the Col le gium In ter - na tion ale Neuro- Psychopharmacologicum (CINP); 1998 Jul; Glas gow, Scot land. 78. Hus sain MZ, Chaudhry ZA. Treat ment of bi po lar de pres sion with topi ra mate: a new an ti con vul sant drug. 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The ef fects of clo zap ine on lev - els of to tal cho les terol and re lated lip ids in se rum of pa tients with schizo phre nia: a pro spec tive study. J Psy chia try Neu ro sci 1999;24: Osser DN, Na jarian DM, Du fresne RL. Ol an zap ine in creases weight and se rum tri - glyc eride lev els. J Clin Psy chia try 1999;60: Sheit man BB, Bird PM, Binz W, Ak inli L, Sanchez C. Olanzapine- induced ele va - tion of plasma tri glyc eride lev els [letter]. Am J Psy chia try 1999;156:1471. Résumé Effets métaboliques des antipsychotiques : prise de poids, diabète sucré et anomalies des lip ides Ob jec tif : Ex am iner la docu men ta tion pub liée et non pub liée dé crivant les change ments de poids, l homéosta sie du glu cose et le mi lieu lipidique avec les an tipsy cho tiques. Méth odes : Une re cher che a été ef fec tuée dans Med line à l aide des termes prise de poids, di abète su cré, cho lesté rol, tri glycé - rides, rispé ri done, clo zap ine, ol an zap ine, queti apine, zi pra si done, prédicteurs, prolac tine, obésité et an tipsy cho tiques clas - siques. On a re cueilli les pub li ca tions, y com pris des ar ti cles orig inaux, des ex po sés de syn thèse, des let tres à la rédac tion, des résumés ou af fiches pré sentés à des as sem blées pro fes sion nelles au cours des 4 der nières années et des bib li og ra phies d ar ti cles pub liés. On a com mu niqué avec des fab ri cants, no tam ment Eli Lilly Can ada Inc, Janssen- Ortho Inc, Pfizer Can ada Inc, As tra - Zeneca Inc, et No var tis Phar ma ceu ti cals pour ob tenir de l in for ma tion médi cale addition nelle. Résul tats : Le sujet de la prise de poids in duite par les an tipsy cho tiques est sous- étudié et il y a rela tive ment peu d études rigoure - use ment con trôlées. La prise de poids comme ef fet sec on daire a été induite par les an tipsy c ho tiques tant clas siques qu atypiques. En outre, cer tains an tipsy cho tiques atypiques sont as so ciés avec le di abète su cré nou veau et des ni veaux ac crus des tri glycé rides sé ri ques. Les prédicteurs de la prise de poids peu vent être l âge, l in dice de masse cor porelle de base, la stimu la tion de l appé tit, l ex po si tion pré cédente aux an tipsy cho tiques et la du rée du traite ment aux an tipsy cho tiques. Con clu sion : Une prise de poids sig ni fi ca tive est dé clarée avec les an tipsy cho tiques atypiques ex is tants. La prise de poids dé crite est très in quiétante pour les pa tients, peut réduire l ob ser vance du traitement, et ac croître le risque re latif de di abète su cré et d hy per tri glycé ridémie. Les médecins qui util is ent ces agents doivent sur veil ler ré gu lière ment le poids, la glycémie à jeun et la courbe lipidique.