The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 30 November 2011

The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 30 November 2011 List of medicines concerned: SECOND-GENERATION ORAL ANTIPSYCHOTICS SOLIAN 100 mg, 200 mg, 400 mg tablet, SOLIAN 100 mg/ml oral solution and generics (amisulpride) ABILIFY 5 mg, 10 mg, 15 mg tablet, 10 mg, 15 mg orodispersible tablet (aripiprazole) LEPONEX 25 mg, 100 mg tablet and generics (clozapine) ZYPREXA 5 mg, 7.5 mg, 10 mg coated tablet, ZYPREXA VELOTAB 5 mg, 10 mg, 15 mg, 20 mg orodispersible tablet and generics (olanzapine) SEROQUEL SR 50 mg, 300 mg, 400 mg sustained-release tablet (quetiapine) RISPERDAL 1 mg, 2 mg, 4 mg tablet, 1 mg/ml oral solution, RISPERDALORO 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg orodispersible tablet and generics (risperidone) Reason for the examination: Re-assessment of the actual benefit and improvement in actual benefit in the treatment of schizophrenia in adults in accordance with the Article R-163-21 of the French Social Security Code. Medical, Economic and Public Health Evaluation Division 1/41

TABLE OF CONTENTS Context and introduction... 3 I. Objective of the Transparency Committee initiative... 4 II. General description... 5 Literature searches... 7 Data on clinical efficacy... 8 I. Data from meta-analyses... 8 I.I. Meta-analyses of studies comparing second-generation antipsychotics with firstgeneration antipsychotics... 8 I.II. Meta-analyses of studies comparing individual oral atypical antipsychotics...11 I.III. The NICE meta-analysis...15 II. DATA FROM PRAGMATIC STUDIES...17 II.I. CATIE study...17 II.II. CUtLASS study...21 II.III. EUFEST study...23 II.IV. Summary...25 Safety... 26 I. DATA FROM META-ANALYSES...26 I.I. Meta-analyses of studies comparing second-generation antipsychotics with firstgeneration antipsychotics...26 I.II. Meta-analyses of studies comparing individual second-generation antipsychotics 28 I.III. Summary...31 II. Pharmacovigilance data...32 II.I. Aripiprazole (ABILIFY)...32 II.II. Amisulpride (SOLIAN)...32 II.III. Olanzapine (ZYPREXA)...32 II.IV. Risperidone (RISPERDAL)...32 II.V. Quetiapine (SEROQUEL SR)...33 II.VI. Clozapine (LEPONEX)...33 Conclusions... 35 Usage data... 37 I. ANALYSIS OF REIMBURSEMENTS BASED ON THE general sample of beneficiaries...37 I.I. Objective...37 I.II. Methods...37 I.III. Results... 38 BIBLIOGRAPHICAL REFERENCES...Erreur! Signet non défini. 2/41

LITERATURE SEARCHES The therapeutic management of schizophrenia is comprehensive, combining psychosocial and educational measures with medicinal treatments. Antipsychotic medicines are the standard pharmacological treatment for schizophrenia. They are used in acute-phase treatment and in maintenance treatment to prevent relapses. In terms of chemical structure, antipsychotics are a heterogeneous group of molecules (phenothiazines, thioxanthenes, butyrophenones, benzamides, etc.). Pharmacologically, they all exert an antagonistic effect on dopamine receptors, in particular D2 receptors. Blockade of D2 receptors contributes to their antipsychotic action but is also responsible for the occurrence of extrapyramidal effects (1). The "atypical antipsychotic" concept was devised after it was found that clozapine could have an antipsychotic effect without triggering extrapyramidal adverse effects. Several molecules were developed in the wake of clozapine and termed "atypical" or secondgeneration antipsychotics (SGA). It was claimed that each one had one or more atypical features compared with conventional or first-generation antipsychotics (FGAs), in particular: no extrapyramidal effects, no hyperprolactinaemia, efficacy in treatment-resistant forms of schizophrenia and efficacy against negative symptoms. The efficacy and adverse effects of these atypical features were attributed to pharmacodynamic factors: reduced affinity for D2 receptors, blockade of other dopamine receptors and action on other types of receptors, in particular serotonin, histamine, cholinergic and alpha-adrenergic receptors (1 3). The reality and impact of these pharmacodynamic factors on therapeutic efficacy remain, however, controversial. In addition, the discovery and confirmation of particularly troublesome adverse effects, in particular metabolic, has cooled the initial enthusiasm for these substances. In France, six antipsychotics defined as "atypical" are currently marketed: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone. Against this background, the HAS decided to re-evaluate the efficacy and safety of these six products in the treatment of schizophrenia in adults. 3/41

I. OBJECTIVE OF THE TRANSPARENCY COMMITTEE INITIATIVE The Transparency Committee of the HAS opened its own enquiry to re-evaluate the actual benefit and the improvement in actual benefit of SGAs in oral form for treating schizophrenia in adults in the light of recent data in the literature and documentation submitted by the manufacturers concerned. This re-evaluation was structured around the following points: Comparison of the efficacy and safety of SGAs as a class versus FGAs; and Comparison of the efficacy and safety of individual SGAs; The following do not come within the scope of this re-evaluation: Injectable SGAs used for rapid control of agitation and behavioural disorders in schizophrenic patients when oral treatment is not appropriate; Long-acting injectable SGAs; and Non-pharmacological management. 4/41

II. GENERAL DESCRIPTION The six SGAs included in the re-evaluation are: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone (cf. Table 1). The indications and actual benefit (AB) and improvement in actual benefit (IAB) levels allocated by the Transparency Committee are set out in detail in Table 2. Table 1. List of the six second-generation antipsychotics included in the re-evaluation INN ATC 2010 Proprietary medicines (oral forms) Date of the initial Marketing Authorisation amisulpride N05AH05 SOLIAN 100 mg, 200 mg, 400 mg tablet, SOLIAN 100 mg/ml oral solution Licence holder of the original medicine 20/01/1986 SANOFI AVENTIS FRANCE and SOLIAN generics clozapine N05AH02 LEPONEX 25 mg, 100 mg scored tablet 20/06/1991 NOVARTIS PHARMA SAS and LEPONEX generics risperidone N05AX08 RISPERDAL 1 mg, 2 mg, 4 mg tablet, 1 mg/ml oral solution, RISPERDALORO 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg orodispersible tablet and RISPERDAL generics olanzapine N05AH03 ZYPREXA 5 mg, 7.5 mg, 10 mg coated tablet, ZYPREXA VELOTAB 5 mg, 10 mg, 15 mg, 20 mg orodispersible tablet and ZYPREXA generics aripiprazole N05AH03 ABILIFY 5 mg, 10 mg, 15 mg tablet, 10 mg, 15 mg orodispersible tablet quetiapine N05AH04 SEROQUEL SR 50 mg, 300 mg, 400 mg sustainedrelease tablet 02/05/1995 JANSSEN CILAG 27/09/1996 ELI LILLY Nederland BV 04/06/2004 OTSUKA PHARMAC EUTICAL EUROPE LTD 23/11/2010 ASTRAZEN ECA 5/41

Table 2. AB and IAB levels voted by the Transparency Committee in the schizophrenia indication INN/PRESENTATIONS Indication wording AB IAB (date of the Transparency Committee opinion) Amisulpride SOLIAN 100 mg, 200 mg, 400 mg tablet, SOLIAN 100 mg/ml oral solution Clozapine LEPONEX 25 mg, 100 mg tablet Risperidone RISPERDAL 1 mg, 2 mg, 4 mg tablet, 1 mg/ml oral solution, RISPERDALORO 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg Olanzapine ZYPREXA 5 mg, 7.5 mg, 10 mg tablet ZYPREXA VELOTAB 5 mg, 10 mg, 15 mg, 20 mg orodispersible tablet Aripiprazole ABILIFY 5 mg, 10 mg, 15 mg tablet, ABILIFY 10 mg, 15 mg orodispersible tablet Quetiapine SEROQUEL SR 50 mg, 300 mg, 400 mg sustained-release tablet "Treatment of schizophrenia." Important "SOLIAN 50 mg tablet, SOLIAN 200 mg tablet and SOLIAN 200 mg/4 ml solution for injection provide a modest level III improvement in actual benefit compared with the neuroleptics used in schizophrenic psychoses." (Re-evaluation opinion of 04/11/1998 following new indication wording and dosages) "LEPONEX is indicated in treatment-resistant schizophrenic patients and in schizophrenic patients who have severe, untreatable neurological adverse effects to other antipsychotic agents, including atypical antipsychotics." Important "In both indications, these proprietary medicines present a major (level II) improvement in actual benefit compared with the usual management." (Opinion in favour of inclusion on the list of medicines reimbursed by National Insurance, dated 20/12/2000) "Treatment of schizophrenia." Important "Compared with haloperidol, the improvement in actual benefit of RISPERDAL is level III, in terms of safety and ease of prescription with a narrow and welldefined dose range." (Opinion in favour of inclusion on the list of medicines reimbursed by National Insurance, dated 05/07/1995) "Treatment of schizophrenia. Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response." "Treatment of schizophrenia in adults and in adolescents aged 15 years and older." Important Important "In terms of efficacy and safety, the improvement in actual benefit is major (level II) compared with haloperidol and minor (level IV) compared with risperidone as improvement in efficacy was only observed for certain subgroups of responders." (Opinion in favour of inclusion on the list of medicines reimbursed by National Insurance, dated 07/01/1998) "No data supplied changes the major level (level II) of improvement in actual benefit compared with haloperidol. Olanzapine (ZYPREXA) does not provide any improvement in actual benefit (level V) compared with risperidone." (Opinion in favour of renewed listing, dated 26/06/2002) "By reducing the incidence of extrapyramidal adverse effects, Abilify provides a level III improvement in actual benefit, in terms of safety, compared with Haldol. By reducing the incidence of weight gain and the effects of the treatment on lipid metabolism, Abilify provides a level IV improvement in actual benefit, in terms of safety, compared with Zyprexa." (Opinion in favour of inclusion on the list of medicines reimbursed by National Insurance, dated 08/12/2004) "Treatment of schizophrenia." Important "In the absence of comparative studies with an active treatment, SEROQUEL SR does not provide an improvement in actual benefit (level V IAB), compared with the other therapies available in this indication." (Opinion in favour of inclusion on the list of medicines reimbursed by National Insurance, dated 08/06/2011) 6/41

LITERATURE SEARCHES The objective of the literature search was to collect meta-analyses, literature reviews and clinical studies comparing oral antipsychotics for the treatment of schizophrenia in adults. The following sources were searched over the period from January 2005 to April 2011: The Medline database; The Cochrane Library; Websites publishing recommendations or evaluation reports; Websites of learned societies relevant to the field under study. This research was supplemented by the experts bibliography, the references cited in the documents analysed and the documentation submitted by the licence holders. 7/41

DATA ON CLINICAL EFFICACY I. DATA FROM META-ANALYSES I.I. Meta-analyses of studies comparing second-generation antipsychotics with first-generation antipsychotics Leucht et al., 2009 (4) compared the efficacy of SGAs and FGAs in schizophrenic patients in a metaanalysis of 150 studies pooling 21,533 patients. Several Cochrane meta-analyses of randomised controlled studies comparing SGAs and FGAs were also published but will not be detailed here since they are largely based on the same studies as those included in the meta-analysis by Leucht et al. (5 9). Meta-analysis by Leucht et al., 2009 (4) The objective of this meta-analysis was to compare the efficacy and safety of SGAs and FGAs in oral form in the treatment of schizophrenia or associated disorders. a. Methods Sources consulted: The search for randomised controlled clinical trials comparing a SGA in oral form with a FGA was conducted between August 2005 and October 2006 using the Cochrane Schizophrenia Group register, the FDA website and the MEDLINE database. Selected studies: The meta-analysis included 150 double-blind randomised clinical studies corresponding to 21,533 patients. The majority of the studies were short-term (twelve weeks or fewer for 81%). Only twelve studies lasted more than six months. The analysis concerned nine SGAs. Only the results concerning amisulpride, clozapine, aripiprazole, risperidone, olanzapine and quetiapine are presented. The main FGAs studied were haloperidol (95 studies) and chlorpromazine (28 studies). Study population: It involved patients with schizophrenia or associated disorders. The average duration of the disease was 11.8 years (standard deviation (SD) 7.7 years) and the average age of the patients was 36.2 years (SD 7.1 years). Endpoints: The endpoints were changes in general symptoms (variation in the total score on the PANSS 1 scale or, if not available, variation in the BPRS 2 score), changes in positive, negative or depressive symptoms, quality of life and relapse rate. The safety profile of SGAs versus FGAs was evaluated on the basis of weight gain, sedation and extrapyramidal adverse effects. The results are presented in standardised mean difference with correction for sample size (Hedges adjustment g factor). 1 PANSS (Positive and Negative Syndrome Scale) is an instrument for evaluating positive and negative schizophrenia symptoms. PANSS is a scale with 30 items, rated from 1 (absent) to 7 (extreme). It allows the scores to be calculated in three categories: positive symptoms (7 items), negative symptoms (7 items) and general psychopathology (16 items). The total score goes from 30 to 210 points. 2 BPRS (Brief Psychiatric Rating Scale) is a general psychopathology scale comprising 18 items rated from 1 (absence) to 7 (maximum frequency). Each BPRS item describes a symptom or behaviour frequently encountered clinically: somatic concerns, anxiety, feelings of guilt, suspiciousness, etc. 8/41

b. Efficacy results Results for efficacy in terms of symptom changes (general symptoms and subscales evaluating positive and negative symptoms and depression) are presented in Figure 1. Figure 1. Efficacy of SGAs versus FGAs for changes in schizophrenic symptoms (Leucht et al., 2009) (4)* * sertindole, ziprasidone and zotepine are not available in France. In this meta-analysis, amisulpride, clozapine, olanzapine and risperidone were more effective than FGAs for improvement in symptoms (standardised mean difference (SMD) = -0.13 to -0.52). These four SGAs were also more effective than FGAs for improvement in positive (SMD = -0.13 to -0.36) and negative (SMD = -0.13 to -0.32) symptoms. 9/41

Aripiprazole and quetiapine were comparable to FGAs for improvement in general symptoms and improvement in negative symptoms. Quetiapine was less effective than FGAs for improvement in positive symptoms (SMD = 0.14; 95% confidence interval (CI) [0.03; 0.26]). Overall, SGAs were more effective than FGAs for improvement in depressive symptoms (SMD = -0.12 to -0.51) except for risperidone, which was comparable to FGAs for this endpoint. Relapse rates were analysed using fourteen long-term studies. Only olanzapine and risperidone were more effective than FGAs for the relapse rate (olanzapine: four studies; n = 1,008; relative risk (RR) = 0.67; 95% CI [0.49; 0.92]; risperidone: five studies; n = 1,174; RR = 0.74; 95% CI [0.63; 0.87]). Amisulpride, aripiprazole and clozapine were comparable to FGAs for the relapse rate. No study comparing quetiapine to FGAs for relapse prevention was included in the meta-analysis. In terms of quality of life, amisulpride and clozapine proved to be more effective than FGAs in one study (amisulpride: one study; n = 194; SMD = -0.13 [-0.60-0.03]; clozapine: one study; n = 311; SMD = -0.24 [-0.46-0.01]). The other SGAs were comparable to FGAs (twelve studies in all). c. Summary This meta-analysis shows that: Four SGAs (amisulpride, clozapine, olanzapine and risperidone) demonstrated greater efficacy than FGAs in improving the positive and negative symptoms of schizophrenia; Aripiprazole and quetiapine were comparable to FGAs, including for changes in negative symptoms, and quetiapine was less effective than FGAs for changes in positive symptoms; SGAs were more effective than FGAs in reducing depressive symptoms except for risperidone, which was comparable to FGAs; Olanzapine and risperidone, but not amisulpride, aripiprazole and clozapine, were more effective than FGAs for the relapse rate. It should be noted that the studies included in the meta-analysis were for the most part of short duration (under twelve weeks) and compared a SGA to haloperidol. The results on safety (extrapyramidal adverse effects, weight gain and sedation) are set out in detail in the "safety" section. 10/41

I.II. Meta-analyses of studies comparing individual oral atypical antipsychotics Leucht et al., 2009 (10) compared the efficacy of individual SGAs in schizophrenic patients in a metaanalysis of 78 studies including 13,558 patients. Several Cochrane meta-analyses also compared the various SGAs in schizophrenic patients but details will not be given here since they are largely based on the same studies as those included in the meta-analysis by Leucht et al. (11 16). Meta-analysis by Leucht et al., 2009 (10) The objective of this meta-analysis was to compare the efficacy of individual SGAs for the treatment of schizophrenia or associated disorders. a. Methods Sources consulted: Publications were searched in the Cochrane Schizophrenia Group register (until May 2007) and in the MEDLINE database (until September 2007). Selected studies: 78 randomised clinical studies (single- or double-blind) comparing SGAs were included, corresponding to 13,558 patients. The meta-analysis concerned nine SGAs. Only results concerning amisulpride (9 studies), clozapine (28 studies), aripiprazole (4 studies), risperidone (44 studies), olanzapine (48 studies) and quetiapine (21 studies) are presented. Study population: It involved patients with schizophrenia or associated disorders. Endpoints: The endpoints were changes in general symptoms (variation in the total score on the PANSS scale), changes in positive and negative symptoms and dropout rates due to lack of efficacy. Results are presented as the weighted mean difference. b. Efficacy results Results for efficacy in terms of changes in general symptoms are presented in Figure 2. Amisulpride: No difference in efficacy was observed between amisulpride and olanzapine (four studies; n = 701) or between amisulpride and risperidone (two studies; n = 291). Aripiprazole: Aripiprazole was less effective than olanzapine (two studies; n = 794; weighted mean difference (WMD) = 5.0; 95% CI [1.9; 8.1]. No difference in efficacy was observed between aripiprazole and risperidone (two studies; n = 372). Clozapine: Clozapine was comparable to olanzapine (seven studies; n = 619), quetiapine (four studies; n = 232) and risperidone (five studies; n = 466) on changes in general symptoms and positive symptoms. For negative symptoms, quetiapine was more effective than clozapine (two studies; n = 142; WMD = 2.2; 95% CI [1.0; 3.5]). According to the authors, however, clozapine doses were low (< 400 mg/day), which could account for these results. 11/41

Olanzapine: Olanzapine was more effective than aripiprazole, quetiapine and risperidone on changes in general symptoms (olanzapine versus aripiprazole: two studies; n = 794; WMD = -5.0; 95% CI [-8.1; -1.9]; olanzapine versus quetiapine: ten studies; n = 1,449; WMD = -3.7; 95% CI [-5.4; -1.9]; olanzapine versus risperidone: fifteen studies; n = 2,404; WMD = -1.9; 95% CI [-3.3; -0.6]). Olanzapine had an efficacy comparable to that of clozapine (seven studies; n = 619) and amisulpride (four studies; n = 701). No difference was observed between olanzapine and other SGAs (amisulpride, clozapine and risperidone) for changes in positive symptoms except for quetiapine, which was less effective than olanzapine. No difference was observed between olanzapine and other SGAs for changes in negative symptoms. Quetiapine: Quetiapine was less effective than olanzapine and risperidone for changes in general symptoms (quetiapine versus olanzapine: ten studies; n = 1,449; WMD = 3.7; 95% CI [1.9; 5.4]; quetiapine versus risperidone: nine studies; n = 1,953; WMD = 3.2; 95% CI [1.1; 5.4]). No difference in efficacy was observed between quetiapine and clozapine (four studies; n = 701). Quetiapine was less effective than olanzapine (six studies; n = 646; WMD = 1.9; 95% CI [1.1; 2.7]) and risperidone (seven studies; n = 1,264; WMD = 1.8; 95% CI [1.2; 2.5]) for changes in positive symptoms. Quetiapine was comparable to olanzapine and risperidone for changes in negative symptoms and was more effective than clozapine (two studies; n = 142; WMD = - 2.2; 95% CI [- 3.5; - 1.0]). Risperidone: risperidone was more effective than quetiapine for changes in general symptoms (nine studies; n = 1,953; WMD = - 3.2; 95% CI [1.1; -5.4]), less effective than olanzapine (fifteen studies; n = 2,404; WMD = 1.9; 95% CI [3.3; 0.6]) and comparable to amisulpride (two studies; n = 291), aripiprazole (two studies; n = 372) and clozapine (five studies; n = 466). No difference was observed between risperidone and other SGAs for changes in negative symptoms. Sensitivity analyses were carried out on the basis of disease stage: In early schizophrenia, no difference in efficacy was observed between the individual SGAs (five studies included); In treatment-resistant schizophrenia, clozapine was compared with olanzapine (seven studies) and risperidone (five studies): no difference in efficacy was observed between clozapine and the other two SGAs (olanzapine and risperidone). 12/41

Figure 2. Comparative efficacy of SGAs on changes in schizophrenia symptoms (total score on the PANSS scale) (Leucht et al., 2009) (10)* * sertindole, ziprasidone and zotepine are not available in France. 13/41

c. Summary This two-by-two comparative meta-analysis of SGAs shows: no difference in efficacy between olanzapine, amisulpride and clozapine for changes in general, positive or negative symptoms evaluated by the PANSS scale. minor differences in efficacy for changes in general symptoms for some of the SGAs evaluated: olanzapine was more effective than aripiprazole, quetiapine or risperidone. Risperidone was less effective than olanzapine but more effective than quetiapine. differences observed between SGAs for changes in general symptoms applied overall to changes in positive symptoms. No difference was observed between SGAs for changes in negative symptoms except for quetiapine, which was more effective than clozapine in two studies with small sample sizes (n = 142). 14/41

I.III. The NICE meta-analysis The National Institute for Clinical Excellence (17) updated its recommendation regarding the management of schizophrenia in March 2009, the previous version having been issued in December 2002. Clinical studies comparing antipsychotics, SGAs or FGAs were systematically reviewed for this purpose. A search was conducted for double-blind randomised clinical studies comparing antipsychotics, FGAs or SGAs between January 2002 and July 2008 in the CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO databases. a. Initial treatment of schizophrenia In the management of early-stage schizophrenia (recent-onset schizophrenia and patients starting an antipsychotic treatment), nine double-blind randomised studies (n = 1,801) comparing oral antipsychotics (SGAs or FGAs) were included: olanzapine versus haloperidol (three studies), olanzapine versus quetiapine (one study), olanzapine versus risperidone (three studies), risperidone versus haloperidol (four studies) and risperidone versus quetiapine (one study). There was no significant difference in clinical efficacy between the various FGAs and SGAs analysed. Safety was consistent with the information reported in the summary of product characteristics. b. Treatment of acute episodes In the management of acute episodes, 71 double-blind randomised studies comparing oral antipsychotics (SGAs or FGAs) were included (n = 16,556). The majority of the studies included an olanzapine (26 studies) or risperidone (30 studies) arm. Amisulpride was tested in six studies, aripiprazole in three studies and quetiapine in seven studies. It cannot be categorically concluded from the data that the antipsychotics differ in terms of their efficacy. Metabolic and neurological adverse effects were consistent with the information reported in the summary of product characteristics. c. Maintenance treatment In the management of patients to prevent relapses, studies were selected that compared a SGA to placebo and a SGA to a FGA. In total, there were eight double-blind randomised studies of SGA (amisulpride, aripiprazole and olanzapine in particular) versus placebo (n = 1,500) and nine studies comparing a SGA (amisulpride, olanzapine and risperidone) with haloperidol (n = 2,035). Although some SGAs show a modest benefit compared with haloperidol in preventing relapses, the data do not warrant recommendation of one antipsychotic over another. The definition of relapse differed from study to study, which also complicates interpretation of the results. Safety was consistent with the information reported in the summary of product characteristics. 15/41

d. Treatment in the event of inadequate response to treatment In the management of treatment-resistant schizophrenias, seven studies comparing clozapine with a FGA (n = 1,066), ten studies comparing clozapine with another SGA (olanzapine and risperidone) (n = 1,064) and five studies comparing SGAs other than clozapine (aripiprazole, olanzapine, quetiapine and risperidone) were included (n = 2,000). Clozapine was the substance associated with the most rigorous demonstration of improved efficacy over FGAs. In the management of patients presenting persistent negative symptoms, analysis included five studies comparing individual SGAs (amisulpride, olanzapine, quetiapine and risperidone) (n = 693) and five studies comparing SGAs (amisulpride, olanzapine, quetiapine and risperidone) with FGAs (haloperidol in three studies) (n = 507). There was no clinically significant difference in efficacy between the various antipsychotics analysed. Safety was consistent with the respective profiles reported in the summary of product characteristics. e. Summary While the previous 2002 report recommended using SGAs as first-line treatment in view of their lower incidence of extrapyramidal adverse effects, NICE concluded that it would henceforth be more appropriate to decide on a case-by-case basis, selecting the substance and formulation best adapted to a specific patient in a given situation based on the efficacy and safety profile. 16/41

II. DATA FROM PRAGMATIC STUDIES Several pragmatic studies sought to compare the effect of SGAs and FGAs in an actual treatment situation. Three studies are set out in detail below: CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) CUTLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) EUFEST (European First Episode Schizophrenia Trial) Table 3. Selected pragmatic studies Name, country CATIE (USA) CUTLASS 1 (UK) CUTLASS 2 (UK) EUFEST (Europe) First author, year Methods Study population Number of patients Lieberman, 2005 (18) Jones, 2006 (19) Lewis, 2006 (20) Kahn, 2008 (21) Double-blind randomised study Randomised study Open-label selection of antipsychotic from the SGA or FGA class, blinded evaluation Randomised study comparing clozapine with other SGAs Open-label selection of antipsychotic from the nonclozapine group, blinded evaluation Open-label randomised study Outpatients or patients admitted to hospital with an acute episode of schizophrenia Schizophrenic patients for whom a change of antipsychotic is being considered Schizophrenic patients who have responded inadequately to treatment Disease duration < 2 years Study treatments 1,493 FGA: perphenazine SGA: ari, clo, ola, que, ris, zipra, combination of antipsychotics 227 FGA: 15 SGA: ami, que, ris, ola, zotepine 136 Clozapine SGA: ami, ola, que, ris, zotepine 498 FGA: haloperidol SGA: ami, ola, que, zipra ami: amisulpride; ari: aripiprazole; clo: clozapine; ola: olanzapine; que: quetiapine; ris: risperidone; zipra: ziprasidone Duration 18 months 12 months 12 months 12 months II.I. CATIE study The objective of the CATIE (18) study was to compare FGAs and SGAs in a real treatment situation in patients with schizophrenia. This pragmatic study sponsored by the National Institute of Mental Health was conducted from January 2001 to December 2004 in 57 sites in the United States. Patients who discontinued the antipsychotic allocated to them could receive other antipsychotics in phases 2 and 3. Only the results of phase 1 will be detailed. a. Methods Study population: It involved inpatients or outpatients aged from 18 to 65 years with schizophrenia (DSM-IV) and able to follow an oral antipsychotic treatment. Patients with a single episode of schizophrenia or treatment-resistant schizophrenia were not included. 17/41

Study design: The patients were randomised under double blinding to receive one of the following antipsychotics: olanzapine (7.5 to 30 mg/day), perphenazine (8 to 32 mg/day), quetiapine (200 to 800 mg/day), risperidone (1.5 to 6.0 mg/day) or ziprasidone (40 to 160 mg/day) (after marketing authorisation was granted in the United States). They were followed up monthly until treatment was discontinued, whether for inefficacy, adverse effects or other reason. Patients with tardive dyskinesia were included in the study but not in the perphenazine arm. Endpoints: The principal endpoint was time to all-cause antipsychotic discontinuation. The main secondary endpoints were the specific reasons for discontinuing treatment and scores obtained on the PANSS scale and the CGI (Clinical Global Impression) scale. Duration of follow-up: The maximum duration of patient follow-up was eighteen months. b. Results In all, 1,493 patients were randomised (cf. Figure 3). The average age was 40 ± 11 years and it involved mostly men (74%). The average duration of antipsychotic treatment was 14 ± 10 years. At the time of inclusion, the current antipsychotic was: olanzapine (22%), quetiapine (7%), risperidone (19%) or a combination of antipsychotics (7%). Figure 3. Number of patients included and reasons for discontinuation in phase 1 of the CATIE study (Lieberman et al., 2005) (18) Treatment discontinuations 18/41

In the intent-to-treat analysis, 74% (1,061 out of 1,432) of patients discontinued the antipsychotic allocated to them before 18 months: olanzapine (64%), perphenazine (75%), quetiapine (82%) and risperidone (74%). The median duration of treatment was 9.2 months for olanzapine and varied from 3.5 months (ziprasidone) to 5.6 months (perphenazine) for the other antipsychotics. The time to treatment discontinuation was longer in the olanzapine group than in the quetiapine groups (HR = 0.63; p<0.001) and risperidone (HR = 0.75; p<0.002). The difference between olanzapine and perphenazine (HR = 0.78; p<0.021) was not significant after correction for the multiple tests (required p<0.017). When the reason for discontinuation was an adverse effect, the time to treatment discontinuation was comparable between the groups. When the reason for discontinuation was lack of efficacy, the time to treatment discontinuation was longer in the olanzapine group than in the perphenazine, quetiapine or risperidone groups. Other efficacy endpoints The scores on the PANSS and CGI scales improved over time in all groups, with no significant difference between the treatment arms. Adverse effects Neurological adverse effects: More patients treated with perphenazine discontinued treatment due to extrapyramidal adverse effects (8% for perphenazine versus 2% to 4% for SGAs). However, no difference was noted between the groups in terms of extrapyramidal or akathisia symptoms or abnormal movements based on the evaluation scales. Weight gain and metabolic disorders: More patients treated with olanzapine discontinued the treatment due to weight gain or metabolic adverse effects (9% for olanzapine versus 1% to 4% for the other groups). Treatment with olanzapine was associated with greater weight gain than in the other groups, with average weight gain of 0.9 kg per month, whereas weight gain was around 0.5 kg per month with quetiapine and risperidone; weight loss was observed with perphenazine and ziprasidone. The proportion of patients presenting weight gain of at least 7% of their baseline body weight was greater in the olanzapine group than in the other groups (30% versus 7% to 16%; p<0.001). Olanzapine was also associated with a greater rise in glycosylated haemoglobin, total cholesterol and triglycerides compared with the other groups. The mean variation in glycosylated haemoglobin compared with the baseline value was 0.4% for olanzapine versus 0.04% (quetiapine) to 0.11% (ziprasidone) for the other groups. The mean variation in total cholesterol compared with the baseline value was +9.4 mg/dl for olanzapine versus -8.2 mg/dl (ziprasidone) to +6.6 mg/dl (quetiapine). The mean variation in triglycerides compared with the baseline value was +40.5 mg/dl for olanzapine versus -16.5 mg/dl (ziprasidone) to +21.2 mg/dl (quetiapine). Other adverse effects: More patients treated with quetiapine reported anticholinergic adverse effects (31% for quetiapine versus 20% to 25% for the other groups). There was no difference between the antipsychotics concerning changes in the QT interval and no reported cases of torsade de pointes. 19/41

The incidence of cataracts was comparable between the various groups. Risperidone was associated with a rise in the prolactin level (variation of +13.8 ng/dl for risperidone versus -1.2 for perphenazine to -10.6 ng/dl for quetiapine). 20/41

II.II. CUtLASS study The CUtLASS (19,20) study was a pragmatic study conducted in fourteen NHS (National Health Services Trust) centres in the United Kingdom in order to compare the efficacy of SGAs and FGAs in a real treatment situation (CUtLASS 1) and the efficacy of clozapine versus other SGAs (CUtLASS 2). 1. CUtLASS 1 a. Methods The objective of CUtLASS 1 was to determine whether the additional costs incurred by SGAs compared with FGAs in the management of schizophrenia were offset in patients by improved quality of life or less frequent use of health services. The hypothesis evaluated was that SGAs lead to a clinically significant improvement in quality of life over a year compared with FGAs. Details of the costefficacy analysis are not given here. Study population: It comprised patients with schizophrenia, schizoaffective disorders or delusional disorders, aged between 18 and 65, with onset of psychotic symptoms at least a month beforehand and whose antipsychotic treatment had been changed on inclusion by the psychiatrist due to an inadequate clinical response or adverse effects with the previous product. Endpoint: The principal endpoint was the total score on Heinrich s QLS quality of life scale 3. Study design: The participants were randomised to receive a FGA or SGA. The psychiatrist had to select a substance in each of these two classes before randomisation. FGAs studied were chlorpromazine, flupenthixol, haloperidol, loxapine, methotrimeprazine, sulpiride, trifluoperazine, zuclopenthixol in oral form or depot preparations. SGAs included risperidone, olanzapine, amisulpride, zotepine and quetiapine. There was no long-acting injectable SGA in this study. b. Results Quality of life CUtLASS 1 included 227 patients, of whom 118 were randomised to receive a FGA and 109 a SGA. Before randomisation, 207 patients had already received a FGA, 44 patients a SGA and 28 patients were taking at least two antipsychotics. At 12 months, 135 patients (59%) were still present in the study, including 64 (54%) in the FGA arm and 71 (65%) in the SGA arm. There was no difference at one year between SGA and FGA for the QLS quality of life scores. Changes in symptoms (PANSS score) Improvement in the symptoms of schizophrenia (total PANSS score, positive symptoms, negative symptoms and general symptoms) was comparable between SGA and FGA. 3 Heinrichs QLS scale (1984): this scale is based on a semi-structured clinical interview of 30 to 45 minutes, at the end of which the clinician evaluates the patient s quality of life. It comprises 21 items, rated from 0 (maximum severity) to 6. Four subscales explore various fields: intrapsychic functioning, interpersonal relationships, social status and regular activities. 21/41

Adverse effects There was no difference between SGA and FGA for the occurrence of adverse effects including neurological adverse effects (with extrapyramidal symptoms, akathisia and tardive dyskinesia). 2. CUtLASS 2 a. Methods The objective of CUtLASS 2 was to compare the effect of clozapine and other SGAs on the quality of life at one year of patients who had responded inadequately to treatment. The patients included were treatment-resistant (failure with at least two antipsychotics) and were randomised to receive either clozapine or other SGA (amisulpride, olanzapine, quetiapine, risperidone or zotepine). The SGA in the "non-clozapine" group was selected by the psychiatrist before randomisation. b. Results Quality of life CUtLASS 2 included 136 patients, 67 of whom were in the clozapine group and 69 in the "other SGA" group. At one year, 54% of patients in the clozapine arm were still treated with clozapine, at an average dose of 333 mg per day. Among the patients treated with SGAs other than clozapine, 57% were still treated with a SGA (four patients changed SGA). On inclusion, patients in the clozapine arm had an average QLS score greater than that of patients treated with other SGAs. Clozapine was not statistically more effective than the other SGAs for improved QLS quality of life scores (p>0.08). Changes in symptoms (PANSS score) Clozapine was more effective than the other SGAs for improvement of schizophrenia symptoms (total PANSS score). Adverse effects There was no difference between clozapine and the other SGAs in terms of the occurrence of adverse effects, including extrapyramidal adverse effects and weight gain. 22/41

II.III. EUFEST study The objective of the EUFEST (European First Episode Schizophrenia) study, which was conducted in collaboration with the EGRIS (European Group for Research in Schizophrenia) (21), was to compare the efficacy of SGAs and haloperidol in actual practice in patients having a first episode of schizophrenia. a. Methods The EUFEST study was a randomised open-label study conducted at fifty sites in Europe between December 2002 and January 2006. Study population: The patients included were aged between 18 and 40 years and had a first episode of schizophrenia or associated disorder defined by the following endpoints: symptoms starting less than two years ago, no antipsychotic treatment or for less than two weeks during the year preceding inclusion or more than six weeks in total. Study design: The patients included were randomised into five arms: haloperidol (1 4 mg/day), amisulpride (200 800 mg/day), olanzapine (5 20 mg/day), quetiapine (200 750 mg/day) or ziprasidone (40 160 mg/day), and then followed up for twelve months. Endpoint: The principal endpoint was discontinuation of the antipsychotic regardless of the cause. The following were also considered as discontinuation events: (1) use of a dose below the recommended dose range; (2) use of a dose above the recommended dose range; and (3) use of another antipsychotic. Duration of follow-up: The study duration was twelve months. b. Results The number of patients randomised was 498, 33% of whom had never received any antipsychotic treatment. The average age of the patients was 26 ± 6 years and most were men (60%). Treatment discontinuation The time to treatment discontinuation was significantly longer for patients treated with SGAs than for those treated with haloperidol: between 1.1 month (ziprasidone) and 6.3 months (olanzapine) for the SGAs versus 0.5 months for haloperidol. The rate of all-cause treatment discontinuation was 72% (63 patients) in the group treated with haloperidol versus 33 53% in the group receiving SGAs (olanzapine: 33%; quetiapine: 53%; amisulpride: 40%; and ziprasidone: 45%). Other efficacy endpoints The reduction in symptoms on the PANSS scale of the order of 60% was similar in the five groups. No difference was observed between treatment groups for the rate of hospital admission, which was between 7% and 23%. 23/41

Adverse effects Neurological adverse effects: A higher proportion of patients treated with haloperidol and ziprasidone presented akathisia and more patients treated with haloperidol developed signs of parkinsonism syndrome: the akathisia rate was 26% for the group treated with haloperidol and 28% in the group treated with ziprasidone versus 10% to 16% in the other groups (olanzapine: 10%; quetiapine: 13%; and amisulpride: 16%); the rate of parkinsonism syndrome was 34% in the group treated with haloperidol versus 6% to 17% in the groups treated with SGAs (amisulpride: 17%; olanzapine: 6%; quetiapine: 11%; and ziprasidone: 16%). Weight gain and metabolic effects: Weight gain was more substantial in the group treated with olanzapine, with average weight gain of 13.9 kg (SD 1.7) after inclusion. Weight gain in the other groups was 7.3 kg (SD 1.8) for haloperidol and in the groups receiving SGAs 9.7 kg (SD 1.7) for amisulpride, 10.5 kg (SD 1.8) for quetiapine and 4.8 kg (SD 1.9) for ziprasidone. More patients on amisulpride developed hyperprolactinaemia (89% in the group treated with amisulpride versus 41% to 50% in the other groups). Metabolic changes (blood sugar, cholesterol, LDL, HDL and triglycerides) were observed in all treatment arms with no significant difference between the groups. The hyperglycaemia rate (fasting blood sugar 5.5 mmol/l) ranged between 18% (haloperidol) and 30% (olanzapine). The hypercholesterolaemia rate (blood cholesterol 5.17 mmol/l) varied between 28% (quetiapine) and 56% (olanzapine) and the hypertriglyceridaemia rate (blood triglycerides 1.69 mmol/l) between 26% (quetiapine) and 39% (olanzapine and haloperidol). 24/41

II.IV. Summary The main results of the CATIE, CUtLASS and EUFEST studies were as follows: In the CATIE study, 64% to 82% of patients discontinued the antipsychotic treatment before eighteen months. Perphenazine (FGA) was comparable to the SGAs (olanzapine, quetiapine, risperidone and ziprasidone) in terms of the time to treatment discontinuation. Discontinuation occurred earlier with quetiapine and risperidone than with olanzapine. There was no difference between the various antipsychotics tested in changes in the CGI and PANSS scores. Discontinuation due to extrapyramidal adverse effects was more frequent with perphenazine than with the SGAs. However, the frequency of extrapyramidal adverse effects evaluated using the evaluation scales was comparable between treatment groups. Treatment discontinuation due to weight gain or metabolic effects was more frequent with olanzapine. Risperidone was associated with a raised prolactin level and quetiapine was more frequently associated with an increase in the occurrence of anticholinergic effects. In the CUtLASS 1 study, there was no overall group difference between the SGA group and FGA group in terms of quality of life (QLS scale). In the CUtLASS 2 study, there was no difference between clozapine and other SGAs in terms of quality of life at one year. Clozapine was more effective than the other SGAs in terms of improvement of schizophrenia symptoms. In the EUFEST study, treatment discontinuation occurred earlier with low-dose haloperidol (1 4 mg/day) than with the SGAs (amisulpride, quetiapine, olanzapine and ziprasidone) in patients with a first episode of schizophrenia. However, the reduction in symptoms (total score on the PANSS scale) was comparable between haloperidol and the SGAs tested (around 60%). In terms of safety, weight gain was frequent for all the antipsychotics tested, with more substantial weight gain with olanzapine. Haloperidol was more frequently associated with the occurrence of extrapyramidal adverse effects. 25/41

SAFETY I. DATA FROM META-ANALYSES Analysis of safety data centred on extrapyramidal adverse effects, weight gain and metabolic adverse effects. It should be noted that safety data details from the pragmatic studies are given above (p. 17 25). I.I. Meta-analyses of studies comparing second-generation antipsychotics with first-generation antipsychotics a. Extrapyramidal symptoms In the meta-analysis by Leucht et al., 2009 (4) (details given above, p. 8), SGAs were compared with FGAs in terms of extrapyramidal adverse effects, using as an endpoint the percentage of patients treated with an antiparkinsonian drug. All the SGAs were associated with a lower rate of prescription of antiparkinsonian drugs than haloperidol, including when haloperidol was used at doses of less than 7.5 mg/day. Clozapine, olanzapine and risperidone were less often associated than low-potency FGAs with concomitant prescription of antiparkinsonian drugs (clozapine: eleven studies; n = 775; RR 0.66 [0.48; 0.91]; olanzapine: two studies; n = 152; RR 0.53 [0.32; 0.89]; and risperidone: two studies; n = 108; RR 0.47 [0.22; 0.99]). Only the data for clozapine allow a rigorous conclusion, with eleven studies enabling evaluation of this endpoint. Quetiapine and amisulpride were comparable to the low-potency FGAs in terms of prescription of antiparkinsonian drugs (amisulpride: one study; n = 30; and quetiapine: two studies; n = 422). The results are detailed in Figure 4. 26/41

Figure 4. Extrapyramidal adverse effects of SGAs versus FGAs (Leucht et al., 2009) (4)* * sertindole, ziprasidone and zotepine are not available in France. b. Weight gain In the meta-analysis by Leucht et al., 2009 (4), amisulpride, clozapine, olanzapine, quetiapine and risperidone were associated with more substantial average weight gain than with haloperidol: amisulpride (N = 2, n = 373; mean difference in weight gain compared with haloperidol = 0.9 kg; 95% CI [0.2; 1.6]), clozapine (N = 3, n = 170; mean difference = 3.4 kg; 95% CI [2.0; 4.9]), olanzapine (N = 9, n = 2,952; mean difference = 3.3 kg ; 95% CI [2.2; 4.4]), quetiapine (N = 3, n = 945; mean difference = 1.4 kg; 95% CI [0.7; 2.1]) and risperidone (N = 9, n = 1,366; mean difference = 1.7 kg ; 95% CI [0.9; 2.4]). Aripiprazole was comparable to haloperidol (N = 2, n = 1,598). SGAs were comparable to low-potency FGAs in terms of weight gain. The results are detailed in Figure 5. 27/41

Figure 5. Effects on weight gain of SGAs versus FGAs (Leucht et al., 2009) (4)* * sertindole, ziprasidone and zotepine are not available in France. No published meta-analysis with a valid methodology has been identified in which SGAs are compared with FGAs for metabolic parameters. I.II. Meta-analyses of studies comparing individual secondgeneration antipsychotics a. Extrapyramidal symptoms A meta-analysis by Rummel-Kluge et al., 2010 (22) compared SGAs in terms of occurrence of extrapyramidal symptoms. A search was conducted for double-blind randomised controlled studies up to September 2007 in the Cochrane Schizophrenia Group register and July 2009 in MEDLINE. The principal endpoint was the rate of prescription of antiparkinsonian medication. Changes in scores on the BAS and SAS 4 scales were selected as secondary endpoints. The analysis comprises 54 studies, 6 of which include amisulpride, 15 clozapine, 34 olanzapine, 11 quetiapine and 32 risperidone. 4 The BAS (Barnes Akathisia Scale) allows akathisia to be assessed with an overall score and three subscores: objective, subjective and distress. The SAS (Simpson-Angus Scale) is intended to assess parkinsonism due to neuroleptics. The rating of its ten items, each comprising five degrees, is based on a simple clinical examination. 28/41

Patients treated with risperidone received antiparkinsonian drugs more frequently than those treated with clozapine, olanzapine and quetiapine (versus clozapine: N = 6; n = 304; RR = 2.57; 95% CI [1.47; 4.48]; versus olanzapine: N = 13; n = 2,599; RR = 1.28; 95% CI [1.06; 1.55]; and versus quetiapine: N = 6; n = 1,715; RR = 1.98; 95% CI [1.16; 3.39]). There was no difference between patients treated with risperidone and those treated with amisulpride (N = 3; n = 586; RR = 1.07; 95% CI [0.72; 1.57]) and aripiprazole (N = 1; n = 83; RR = 1.68, 95% CI [0.89; 3.17]). Patients treated with quetiapine received antiparkinsonian treatment less frequently than those treated with olanzapine and risperidone (versus olanzapine: N = 6; n = 1,090; RR = 0.49, 95% CI [0.3; 0.79]; versus risperidone: N = 6; n = 1,715; RR = 0.5 95% CI [0.3; 0.86]). The results are presented in Figure 6. Figure 6. Extrapyramidal adverse effects of SGAs (Rummel-Kluge et al., 2010) (22)* * ziprasidone and zotepine are not available in France. 29/41

b. Weight gain, metabolic adverse effects A meta-analysis by Rummel-Kluge et al., 2010 (23) compared metabolic safety and weight gain of SGAs. A search of double-blind randomised controlled studies was conducted up to September 2007 in the Cochrane Schizophrenia Group register and July 2009 in MEDLINE. The analysis comprises 48 studies lasting 2 to 6 months, 6 of which include amisulpride, 5 aripiprazole, 11 clozapine, 37 olanzapine, 11 quetiapine and 32 risperidone. The principal endpoint was weight variation. Figure 7. Comparison of SGAs in terms of weight gain (Rummel-Kluge et al., 2009) (23)* * sertindole and ziprasidone are not available in France. 30/41

Olanzapine induced more weight gain than other SGAs except for clozapine, which was comparable to olanzapine: amisulpride (N = 3, n = 671; mean difference = 2.11 kg; 95% CI [1.29; 2.94]), aripiprazole (N = 2, n = 656; mean difference = 3.9 kg; 95% CI [1.62; 6.19]), quetiapine (N = 7, n = 1,173; mean difference = 2.68 kg; 95% CI [1.10; 4.26]) and risperidone (N = 16, n = 2,302; mean difference = 2.44 kg; 95% CI [1.61; 3.27). Risperidone led to more substantial weight gain than amisulpride (N = 3; n = 585; mean difference = 0.99 kg; 95% CI [0.37; 1.61]). Among the other SGAs compared, no difference in weight gain was observed between aripiprazole and risperidone (N = 2; n = 283), clozapine and olanzapine (N = 8; n = 611), clozapine and quetiapine (N = 1; n = 27), and quetiapine and risperidone (N = 7; n = 1,446). Olanzapine led to a greater mean increase in blood sugar (compared with the study inclusion value) than that associated with other SGAs except for clozapine, which did not differ from olanzapine: amisulpride (N = 2; n = 406, mean difference = 7.3 mg/dl; 95% CI [6.99; 7.62]), aripiprazole (N = 3; n = 1,487, mean difference = 4.13 mg/dl; 95% CI [1.68; 6.58] and risperidone (N = 9; n = 1,303, mean difference = 5.94 mg/dl; 95% CI [2.59; 9.3]). Olanzapine led to a more substantial rise in cholesterol than aripiprazole (N = 2; n = 789; mean variation 15.35 mg/dl; 95% CI [9.08; 21.62]) and risperidone (N = 9; n = 1,802, mean variation 12.92 mg/dl; 95% CI [8.22; 17.62]). Risperidone led to a more substantial rise in cholesterol than aripiprazole (N = 1; n = 83; mean variation 22.3 mg/dl; 95% CI [4.91; 39.69]). I.III. Summary In terms of extrapyramidal adverse effects, the meta-analysis by Leucht et al. (4) showed that the use of antiparkinsonian medication was less frequent with SGAs than with haloperidol, including when the latter was used at doses of less than 7.5 mg mg/day. In this meta-analysis, the SGAs were comparable to the low-potency FGAs for use of antiparkinsonian drugs except for clozapine and, to a lesser extent, olanzapine and risperidone. The meta-analysis by Rummel-Kluge et al. (22) showed that SGAs are not a homogeneous group in terms of the occurrence of extrapyramidal effects: risperidone was associated with more frequent use of antiparkinsonian drugs than clozapine, olanzapine and quetiapine; no difference was observed with aripiprazole and amisulpride. Although the differences observed were slight, they may be important in individual patients and should be taken into account when selecting an antipsychotic. In terms of weight gain, the meta-analysis by Leucht et al. (4) showed that clozapine, olanzapine, quetiapine, risperidone and amisulpride were associated with more substantial mean weight gain than with haloperidol. No difference was observed between aripiprazole and haloperidol. The twoby-two comparison of the SGAs for weight gain showed that olanzapine entailed a more substantial risk of weight gain than the other SGAs except for clozapine, which was comparable to olanzapine (23). In terms of metabolic safety, olanzapine led to a greater mean increase in blood sugar and cholesterol than with other SGAs except for clozapine, which was comparable to olanzapine. 31/41