Comparing tolerability profile of quetiapine ...

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by Albany College of Pharmacy on 06/19/15 For personal use only.

Original Research

1.

Introduction

2.

Methods

3.

Results

4.

Discussion

5.

Conclusion

Comparing tolerability profile of quetiapine, risperidone, aripiprazole and ziprasidone in schizophrenia and affective disorders: a meta-analysis Hoda Moteshafi & Emmanuel Stip† †

De´partement de Psychiatrie, Faculte´ de Me´decine, Universite´ de Montreál, Montreal, Quebec, Canada

Objective: Second-generation antipsychotics (SGAs) are extensively prescribed for psychiatric disorders. Based on clinical observations, schizophrenia (SCZ) and affective disorder (AD) patients can experience different SGA side effects. The expanded use of SGAs in psychiatry suggests a need to investigate whether there is a difference in the incidence and severity of side effects related to diagnosis. Methods: A comprehensive literature search was conducted to identify studies reporting side effects of four common prescribed SGAs (aripiprazole, quetiapine, risperidone and ziprasidone) in the treatment of SCZ or AD. Randomized controlled trials were included in this study if they administered oral SGAs as a monotherapy, in adult patients. The metabolic and extrapyramidal side effects were collected separately for each group, and then were combined in a meta-analysis. Results: 80 studies were included in the analysis (N = 14,319). Quetiapine treatment induced significantly higher low-density lipoprotein (LDL) and total blood cholesterol mean change in the SCZ group, relative to the AD group. Based on the results, the incidence of extrapyramidal side effects was more frequent in the AD group. Aripiprazole treatment led to significantly more akathisia incidence in the AD group, compared with the SCZ group. Conclusion: The results suggest that SCZ patients may be more vulnerable to some SGA-induced metabolic disturbances, in which lifestyle risk factors and possible inherent genetic vulnerabilities may play a role. Most of the studied SGAs caused more movement disorders in AD patients than SCZ. It might be that an antipsychotic induces severity of side effect according to the phenotype. Keywords: affective disorders, extrapyramidal symptoms, meta-analysis, metabolic syndrome, schizophrenia, second-generation antipsychotics Expert Opin. Drug Saf. (2012) 11(5):713-732

1.

Introduction

Second-generation antipsychotics (SGAs) have become a first-line medication in the treatment of psychotic disorders, such as schizophrenia (SCZ) and schizoaffective disorders [1,2] and a serious consideration in the treatment of several affective disorders (ADs) [3,4]. Several studies have proposed SGA monotherapy or combination therapy in controlled trials, comparing them with placebo or first-generation antipsychotics (FGAs) [5-8]. However, the treatment with SGAs has been associated with concerns about metabolic side effects, which can induce long-term 10.1517/14740338.2012.712682 © 2012 Informa UK, Ltd. ISSN 1474-0338 All rights reserved: reproduction in whole or in part not permitted

713


H. Moteshafi & E. Stip

consequences such as metabolic syndrome, diabetes mellitus and cardiovascular diseases (CVD). Patients with severe mental diseases are two to three times more at risk for obesity, metabolic syndrome and related morbidity and mortality compared with general population [6,9]. Factors that affect patients with severe mental illnesses and contribute to metabolic syndrome and diabetes mellitus include genetic predisposition to certain pathologies such as weight gain, diabetes mellitus and lipid abnormalities [10-12]; sedentary life style and poor diet [13,14]; high levels of smoking, alcohol intake and drug abuse [15,16]; limited access to regular healthcare services [17] and potential metabolic adverse events which occur during antipsychotic treatment [13,18,19]. An increased number of evidences have suggested that certain SGAs are associated with increased risk of metabolic complications such as obesity, glucose intolerance and dyslipidemia, which are risk factors for developing diabetes mellitus, metabolic syndrome, CVD and premature death. Thus, the physical health of mental disorder patients is further influenced by SGAs treatment. The SGAs side effects on physical health have become an important issue in mental illnesses’ treatment [20]. These side effects are especially important in vulnerable population, such as drug-naı¨ve first-episode patients, children and adolescents [21]. Literature findings revealed that individual SGAs differ in their liability to induce metabolic disturbances [22-24]. Generally, clozapine and olanzapine are known to be associated with the highest risk of clinically significant weight gain, followed by quetiapine, risperidone and sertindole [22-24]. Amisulpride, ziprasidone and aripiprazole have the lowest risk for clinically significant weight gain [22-24]. Furthermore, based on the published data olanzapine and clozapine also increase the risk of diabetes and dyslipidemia. The findings about quetiapine and risperidone are controversial and need more investigations, while amisulpride, ziprasidone and aripiprazole do not seem to significantly change blood glucose levels or lipid profiles [2,21-23,25,26]. Extrapyramidal symptoms (EPS) including dystonia, parkinsonism and akathisia are other common side effects associated with antipsychotic treatment [27]. The incidence of movement disorders related to the use of antipsychotics is thought to occur due to D2 receptors blockade in the striatum. The drugs with higher affinity for D2 receptors cause higher rate of EPS [28]. Although, SGAs have a more favorable EPS profile than FGAs [29,30], studies have shown that EPS, including akathisia [31] and tardive dyskinesia (TD) [32], are also observed with SGAs. Acute development of EPS in several studies has been identified as an important risk factor for later development of TD in SCZ patients [33,34]. While some studies have shown the similar risk of SGAsinduced EPS in bipolar patients (BP) and SCZ, other studies have reported more vulnerability to movement disorders in BP [27,35,36]. SCZ and ADs both are polygenic and multifactorial complex disorders in which a myriad of different genes are potentially 714

involved. Even though BP and SCZ differ in neurobiology and phenomenology [37-39], these disorders share some genetic features [40-43]. Although the pathophysiology of both disorders remains unclear, in recent years, the investigation of the factors which contribute to the SGA’s tolerability profiles in AD and SCZ has just emerged [19,44]. Based on broad SGA prescriptions for different diagnoses in psychiatry, it would be interesting to see whether the side effects have a different expression and severity according to phenotype. In a previous article [45], the authors examined the potential difference in olanzapine-induced metabolic side effects between SCZ and AD patients, in which they found more vulnerability in SCZ patients regarding these side effects. However, only the weight gain was significantly higher in schizophrenic patients compared with AD patients [45]. As only olanzapine side effects were considered in the prior work [45], the current meta-analysis extends the earlier work to other most frequently prescribed SGAs: quetiapine, risperidone, ziprasidone and aripiprazole. This meta-analysis illuminates the relative side-effect profiles of SGAs when prescribed for SCZ and AD patients, mainly bipolar disorder. The study covers the result of the first meta-analysis comparing metabolic and extrapyramidal side effects of SGAs in the two groups of patients. Olanzapine is among the most commonly used antipsychotic medications for both SCZ and ADs. Recently, a functional magnetic resonance imaging (fMRI) study conducted by Stip et al. [46]. suggested that olanzapine treatment in SCZ patients induce changes in neuronal activity related to food information processing. These changes correlate with some metabolic disturbances and with cognitive measurements related to appetite regulation. It is not known if there is a similar mechanism in AD patients treated with this medication. The authors’ group only documented that there are differences between normal population and SCZ patient in terms of appetite information processing [47]. Ideally, a thorough metaanalysis of the metabolic liability of various commonly used antipsychotic medications between two diagnostic groups in one publication would have provided a better perspective to the readers; however, the specific data on the most prescribed one needed more detailed analysis and discussion. For this reason, the authors presented olanzapine results in one separate article [45]. Even if olanzapine is not included in this analysis, they present summarized data of olanzapine when it is necessary to incorporate to the general discussion or the global results description. In the previous work [45], 33 studies (4831 patients) that address olanzapine monotherapy of adults with SCZ and AD were included in the analysis. Tolerability outcomes show that olanzapine elevates body weight, triglycerides, low-density lipoprotein (LDL) and glucose and total cholesterol levels in both SCZ and AD patients. Moreover, olanzapine treatment produced significantly more weight gain in SCZ patients than in the AD patients. Based on the results, an incidence of parkinsonism was significantly more frequent in the SCZ group than in the AD group which was unexpected [45].

Expert Opin. Drug Saf. (2012) 11(5)

Comparing tolerability profile of quetiapine, risperidone, aripiprazole and ziprasidone in schizophrenia

A difference in severity of side effects could mean that a phenotype per se influences a medication’s tolerability profile. The authors hypothesized that phenotype of disease may affect induction and severity of side effects. With the increasing use of SGAs in psychiatry, this investigation is valuable, not only to inform clinicians, but also to provide clues to the pathophysiology of SCZ-spectrum and ADs. 2.

Methods

Data source Systematic reviews of the literature on four antipsychotics (quetiapine, risperidone, ziprasidone and aripiprazole) in the treatment of SCZ and ADs that reported randomized controlled trials (RCTs) were performed. The search engines were PsycINFO (1967 -- 2010), PubMed (MEDLINE), EMBASE (1980 -- 2010) and clinicaltrials.gov website. The authors performed a systematic literature review using the Medical Subject Headings (MeSH) terms. The keywords used for the search were quetiapine, risperidone, ziprasidone or aripiprazole in conjunction with schizophrenia or affective disorder, bipolar disorder, major depression, bipolar mania, unipolar depression. There were no limitations on language. A hand search of published review articles, as well as cross-referencing, was carried out to gather further data. It is important to mention that at this stage, the authors could not find any article that reports SGAs side effects for both SCZ and AD patients; therefore, they searched for articles that report SGAs side effects in either SCZ or AD groups; the results were then compared together. The authors of the selected studies that met inclusion criteria were contacted to provide unreported or additional data. Two reporters independently checked all reports for inclusion and exclusion criteria.


2.1

Inclusion criteria Studies were searched for two diagnostic groups: ADs and SCZ. Inclusion criteria were studies that contained i) adults patients (18 -- 65 years old) who had a diagnostic of SCZ or ADs such as major depression, bipolar mania or bipolar depression; ii) RCTs (open-label or double-blind); iii) oral monotherapy treatment with quetiapine, risperidone, ziprasidone or aripiprazole; iv) fixed and flexible-dose studies with a duration of 3 weeks or longer and v) reported data on metabolic or extrapyramidal side effects. 2.1.1

Exclusion criteria Trials in both groups were left out if they contained i) combination therapy of any agent with another medication such as antimanic or antidepressant; ii) other psychotic diagnoses such as schizoaffective or schizophreniform disorders; iii) incomplete or unavailable data even after contacting author; iv) study groups of children or adolescents; v) non-randomized design or vi) treatment with depot antipsychotics. 2.1.2

Data extractions and outcome parameters Two reviewers (H.M. and E.S.) independently checked abstracts and chose related articles, then one reviewer (H.M.) extracted data while checking the inclusion criteria. Trial abstracts were screened initially and then in the second step full-texts were reviewed. Data from SCZ and ADs group were compared. The data extractions were separated along two dimensions: i) clinically important metabolic side effects such as change of weight, blood glucose and cholesterol levels. Weight change was reported as the change in kilograms from baseline to end point; the changes in other metabolic parameters were defined as the change from baseline to end point in mg/dl; ii) some EPS-related adverse events (such as akathisia and parkinsonism), as well as the use of antiparkinson medication for treating EPS were checked. The outcome variable was incidence of EPS-related side effects, as measured by treatment-emergent adverse event data. 2.2

Meta-analytic calculations Using comprehensive meta-analysis (CMA) software version 2.2.05 [48], effect size estimates for each side effect was calculated. For each group of subjects, AD and SCZ patients, effect size estimates were calculated from i) mean and standard deviation (SD) of metabolic side effects or ii) events rates for EPS. Continuous outcomes (metabolic side effects) were analyzed by estimating means and confidence intervals for each group of subjects: SCZ and ADs. Also, dichotomous outcomes (EPS) were analyzed by estimating event rate and confidence intervals for each group of subjects. The effect size estimates for all studies in each patient group (SCZ or AD) were pooled together to yield an overall effect size estimate for each group. Then, CMA was used to compare the point estimate of each group to see whether the difference between the points was significant or not. The level of significance for the effect size estimates was set at p = 0.05. For all analyses, effect size estimates were pooled with the random-effects model, which is stricter than fixed-effects model and permits population-level inferences as well [49]. Meanwhile, the authors assessed the heterogeneity of study with the I-squared statistic, supposing that I2 statistics greater than 50% proposed considerable heterogeneity. 2.3

Subanalyses and addressing potential confounding factors

2.3.1

Subanalyses, including between-group differences, were carried out for potential confounding factors in age, sex ratio and medication daily dose. The effects of treatment duration on the results were examined by performing subgroup analyses including short-term (< 12 weeks) and long-term studies (> 12 weeks), separately. The authors also performed mixed-effects meta-regression to investigate whether percentage of male patients involved in studies were correlated with the differences in effect size and to explain potential heterogeneity.


715


1732 of records identified through database searching for schizophrenia disorder

Number of records identified through each database: PubMed (566), PsycInFO (87), EMBASE (1079)


941 of records after duplicates removed 791 reports retrieved for more detailed evaluation 744 of records excluded with these reasons: type of study, type of publication, treatment type, or not available data 47 studies included in the review: quetiapine(15), ziprasidone(8), aripiprazole(9), and risperidone(15)

Figure 1. Flow diagram describing the search process for schizophrenia group.

3.

Results

Literature searching results A total of 3615 abstracts were identified initially in which 1732 were related to the SCZ group and 1883 to the AD group. Among these, 3535 were discarded on the basis of duplication or evaluating abstract and article, according to the following criteria: i) type of article/study (e.g., case study, review, letter to the editor and crossover study); ii) type of population (e.g., non-randomized, non-SCZ patients, age range); iii) treatment type (e.g., combination therapy or depot administration); iv) incomplete or non-available data. As a result, 80 studies (n = 14,319) were accepted for both groups: for SCZ patients N = 47, n = 7700 and for AD group N = 33, n = 6619 (‘N’ refers to the number of articles whereas ‘n’ is the number of patients). SCZ group articles contained 15 for quetiapine [50-64], 9 for aripiprazole [65-73], 8 for ziprasidone [57,74-80] and 15 for risperidone [51,54,57,60,61,64,81-89]. AD group articles contained 16 for quetiapine [3,90-104], 9 for aripiprazole [105-113], 4 for ziprasidone [114-117] and 4 for risperidone [118-121]. More information on the sorting process in each group is shown in Figures 1 and 2. Cross-referencing of included studies did not add more studies in the meta-analysis. In addition, Tables 1 and 2 provide details of demographic characteristics among studies included in the meta-analysis. It should be mentioned that the AD group is a heterogeneous group and for this reason the authors added a column in Table 2 to specify the type of AD in each study, 3.1

716

considering the inclusion criteria. The percentage of patients diagnosed with major depressive disorder (MDD) in the quetiapine treatment group was 32, and the rest of 68% was for bipolar I or II disorder (with or without rapid cycling). In the aripiprazole treatment group, 28% of the patients were diagnosed with MDD, while the rest had bipolar I disorder with acute manic or mixed episode. In addition, 13% of patients in the risperidone treatment group had coexisting psychotics and depressive symptoms, while 78% were diagnosed with bipolar I disorder (manic or mixed episode). Finally, all patients in the ziprasidone treatment group were diagnosed with bipolar I disorder (manic or mixed episode). Outcome results First outcome: metabolic changes 3.2.1.1 Weight gain 3.2

3.2.1

In quetiapine treatment, 10 studies for the SCZ (n = 1683) and 12 for the AD group (n = 3411) were reviewed for weight changes. Even though the increase from baseline was more in SCZ group, there was no statistically significant difference between the two groups (1.72 vs 1.15 kg; p = 0.108). For aripiprazole treatment, four studies in the SCZ (n = 1493) and six in the AD group (n = 844) were checked. The analysis revealed a slight decrease from baseline in the SCZ group and an increase in weight from baseline for the AD group; however, there was no statistically significant difference between the two groups (-0.4 vs 0.49 kg, respectively; p = 0.109).



1883 of records identified through database searching for affective disorders

Number of records identified through each database: PubMed (1091), PsycINFO (76), EMBASE (714) Clinicaltrials.gov website(2)


1502 of records after duplicates removed 381 reports retrieved for more detailed evaluation 348 of records excluded with these reasons: type of study, type of treatment publication type, or not available data 33 studies included in the review: quetiapine(16), ziprasidone(4), aripiprazole(9), and risperidone(4)

Figure 2. Flow diagram describing the search process for affective disorders group.

For risperidone, 13 studies in the SCZ (n = 1278) and two in the AD group (n = 272) were examined. Even though the analysis revealed an increase from baseline in both groups, there was no statistically significant difference between the two disorders (1.32 vs 1.55 kg, for SCZ and AD, respectively; p = 0.486). Despite checking all articles for ziprasidone, the authors could not find enough data related to its monotherapy and metabolic side effects. Therefore, they were not able to compare any metabolic parameters for this agent. In addition, for risperidone treatment the data were only available on weight changes. Thus, the rest of metabolic changes will only be reported for quetiapine and aripiprazole treatment. Cholesterol change Quetiapine increased blood cholesterol levels 8.05 mg/dl in SCZ group (N = 4, n = 1473) and decreased cholesterol level in AD group (N = 7, n = 2433) to 2.8 mg/dl. The SCZ group showed significantly more cholesterol increase than the AD group (p = 0.000). Details are shown in Figure 3. For aripiprazole, two studies in the SCZ (n = 393) and two in the AD group (n = 360) were examined for changes in blood cholesterol levels. Aripiprazole decreased the levels of cholesterol in both groups. However, the difference between the two groups was not significant (-5.76 vs -3.52 mg/dl, for SCZ and AD, respectively; p = 0.629). 3.2.1.2

Glucose change For quetiapine, 5 studies (n = 1553) in the SCZ group and 10 (n = 3214) in the AD group were checked for changes in 3.2.1.3

blood glucose levels. Quetiapine increased blood glucose levels similarly in both groups (4.01 vs 3.85 mg/dl, for SCZ and AD, respectively; p = 0.927). Aripiprazole increased blood glucose levels in the SCZ (N = 2, n = 441) and the AD groups (N = 2, n = 360). Mean change was 2.02 mg/dl in the SCZ versus 3.51 mg/dl in the AD groups, with no significant difference between the two groups (p = 0.490). Triglyceride change For quetiapine, four studies (n = 1269) in the SCZ and seven studies (n = 2342) in the AD group were examined for changes in blood triglyceride levels. The analysis revealed an increase in triglyceride levels in both groups; however, the difference between the groups was non-significant (17.57 vs 7.93 mg/dl, for SCZ and AD, respectively; p = 0.099). 3.2.1.4

LDL change Quetiapine increased mean LDL levels in SCZ group (N = 3, n = 1001) up to 5.00 mg/dl and decreased LDL level in AD group (N = 7, n = 2427) to 2.78 mg/dl. This change on LDL levels was significant between the two groups (p = 0.000). Details are shown in Figure 4. 3.2.1.5

HDL change The authors could not find enough studies to compare highdensity lipoprotein (HDL) changes among treatment groups. 3.2.1.6


717


Table 1. Demographic characteristics among SCZ studies included in the meta-analysis.


Medication/ Study (Ref.) Quetiapine Riedel et al. [61] Riedel et al. [60] Arvanitis and Miller [50] Borison et al. [52]. Kahn et al. [56] Lieberman et al. [57] Lindenmayer et al. [58] Peuskens et al. [59] Small et al. [63] Zhong et al. [64] Conley et al. [54] Atmaca et al. [51] Buckley et al. [53] Copolov et al. [55] Sirota et al. [62] Aripiprazole Kolotkin et al. [71] Cutler et al. [66] Kasper et al. [69] Kerwin et al. [70] Kane et al. [67] McQuade et al. [72] Pigott et al. [73] Kane et al. [68] Chrzanowski et al. [65] Ziprasidone Breier et al. [75] Sacchetti et al. [80] Lieberman et al. [57] Kane et al. [78] Olie´ et al. [79] Arato et al. [74] Hirsch et al. [77] Cutler et al. [76] Risperidone Liberman et al. [57] Yang et al. [89] Hwang et al. [84] Zhong et al. [64] Riedel et al. [61] Riedel et al. [60] Dollfus et al. [83] Sechter et al. [88] Bondolfi et al. [82] Azorin et al. [81] Atmaca et al. [51] Saddichha et al. [87] Peuskens et al. [86] Conley et al. [54] Lin et al. [85]

Age (mean ± SD), year

Dose (mean ± SD), mg/day

Male/Female, number

30.6 ± 10.9 36.69 ± 11.71 37.4 ± 9.4 36 ± 9 34.3 ± 10 40.9 ± 11.2 39.2 ± 10.3 37 36.5 ± 9 40.2 ± 10.8 43.7 ± 5.9 30.1 ± 8.4 39 ± 11.1 37 ± 10 38.3 ± 12.2

589.7 586.8 ± 169.1 75, 150, 300, 600, 750 307 400, 600, 800 XR/400 IR 543.4 300, 600, 800 XR/300, 600 IR 674 250, 750 525 ± 231 463.6 ± 50.5 535.7 ± 110.5 600 455 ± 174 637.2 ± 121.1

12 8 6 6 6 72 6 52 6 8 12 6 8 6 12

15/7, 22 10/6, 16 191/67, 258 48/6, 52 277/181, 458 255/82, 337 310/110, 420 49/35, 84 139/51, 190 260/78, 338 10/2, 12 6/8, 14 38/16, 54 158/63, 221 15/4, 19

38.1 40.5 37.3 38.1 42.6 38.6 42.2 37.3 41.7

10 -- 30 2, 5, 10 29.01 18.7 28.8 25.1 15 19.3 15 -- 30

26 6 52 26 6 26 26 28 52

165/113, 278 216/63, 279 511/350, 861 169/115, 284 114/40, 153 114/42, 156 84/71, 155 190/95, 285 59/45, 104

38.2 ± 12.1 41.6 ± 10.2 40.1 ± 11 35.6 ± 9.5 39.4 50 39.2 40 ± 9.9

115.96 ± 39.91 142 ± 23 112.8 153.8 ± 17 118 40, 80, 160 116.5 160

28 18 78 6 12 52 28 4

172/99, 271 52/21, 73 129/56, 185 103/49, 152 41/19, 60 144/63, 207 92/56, 148 113/36, 149

40.6 ± 11.3 35.97 ± 10.15 34.1 ± 9.9 39.6 ± 10.8 39.3 ± 12.3 39.6 ± 12.4 39.6 ± 10 38.4 ± 10.7 38.3 ± 12.9 39.5 ± 11.3 27.9 ± 7.8 26.7 ± 6.3 37 ± 12 46.3 ± 8.7 38

3.9 4.09 ± 1.56 6.88 ± 1.54 6 ± 1.8 4.9 5.1 ± 1.4 6 ± 2.1 6.92 ± 2.14 6.4 ± 2.1 9±4 6.7 ± 3.6 4.5 ± 1.2 8 4.31 ± 0.63 4

72 8 6 8 6 12 8 24 8 12 6 6 8 12 6

115/46, 161 194/87, 281 25/11, 36 20/18, 38 94/46, 140 16/19, 35 11/6, 17 14/10, 24 244/92, 336 17/4, 21 11/18, 29 46/30, 76 180/97, 277 85/39, 124 24/18, 42

± 10.8 ± ± ± ±

11.7 10.8 12.4 10.6

± 10.4 ± 12.2

SCZ: Schizophrenia; SD: Standard deviation.

718

Treatment duration, week




Table 2. Demographic characteristics among ADs studies included in the meta-analysis. Medication/ Study (Ref.)

Age (mean ± SD), Dose (mean ± SD), Treatment duration, Male/Female, year mg/day week number

Quetiapine McElroy et al. [98] Bowden et al. [3] Endicott et al. [94] Altamura et al. [90] McElroy et al. [97] Weisler et al. [103] Cutler et al. [93] Young et al. [104] Calabrese et al. [92] Suppes et al. [100] Thase et al. [101] Langosch et al. [95] Liebowitz et al. [96] McIntyre et al. [99] Vieta et al. [102] Bortnick et al.§ [91]

38.4 38 37.1 ± 11.1 50.6 ± 8 34 ± 11.2 40.9 ± 11.6 41.25 ± 12.1 42.5 36.95 ± 11.3 39 ± 11.3 37.7 ± 10.7 45.4 ± 11 45.4 ± 11.2 42.8 34.7 43.3 ± 10.5

300, 600 584 300, 600 157.7 ± 157.6 232 50, 150, 300 150, 300 XR 300, 600 300, 600 300 XR 300, 600 465 ± 167 176.6 ± 95.5 XR 600 300, 600 162.2 ± 96 XR

8 12 8 52 8 8 6 8 8 8 8 52 52 12 8 8

179/282, 461 60/47, 107 308/390, 698 5/9, 14 9/10, 19 220/302, 522 126/168, 294 192/326, 518 150/192, 342 45/88, 133 137/169, 306 6/16, 22 132/255, 387 37/64, 101 32/41, 73 52/95, 147

Bipolar Bipolar Bipolar Bipolar Bipolar MDDz MDDz Bipolar Bipolar Bipolar Bipolar Bipolar MDDz Bipolar Bipolar MDDz

Aripiprazole Sachs et al. [111] Vieta et al. [112] CN138-096{ [105] CN138-146{ [106] Keck et al. [108] Keck et al. [109] Kemp et al. [110] El Mallakh et al. [107] Young et al. [113]

40.4 ± 10.5 42.6 ± 11.9 39 ± 11 41 ± 12 39 ± 13.2 40.5 ± 12.7 38.2 ± 12.8 40.3 ± 11.5 40.5

27.7 15 -- 30 17.6 ± 8.3 15.5 ± 7.5 24.3 27.9 15 -- 30 15, 30 22

3 12 8 8 26 3 26 3 12

69/68, 137 76/99, 175 71/115, 186 75/112, 187 30/48, 78 59/71, 130 27/51, 78 128/139, 267 72/95, 167

Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar Bipolar

I I I I I I I I I

disorder disorder disorder & MDDz disorder & MDDz disorder disorder disorder disorder disorder

Ziprasidone Keck et al. [114] Keck et al. [115] Vieta et al. [117] Potkin et al. [116]

39 ± 10.6 38.9 ± 11 38.5 ± 11.6 38.9 ± 11.6

130.1 ± 34.5 125.2 ± 31.9 121.4 112

3 52 9 3

73/58, 131 61/66, 127 108/70, 178 68/71, 139

Bipolar Bipolar Bipolar Bipolar

I I I I

disorder disorder disorder disorder

41 ± 12.2

8 ± 1.45

6

25/37, 62

41.3 ± 13.1 38.1 ± 11.9 34.7 ± 12

4.1 ± 1.8 4.1 ± 1.4 5.6 ± 1.2

12 3 3

83/71, 154 71/63, 134 99/47, 146

Psychotic depressive symptoms Bipolar I disorder Bipolar I disorder Bipolar I disorder

Risperidone Muller-Siecheneder et al. [120] Smulevich et al. [121] Hirschfeld et al. [118] Khanna et al. [119]

Diagnostic type

I I I I I

disorder disorder disorder disorder disorder

I I I I I

disorder disorder disorder disorder disorder

I disorder I disorder

z

Major depression disorder. In Bortnick et al. [91], the data were available online in 2010, but the paper was published in 2011. { Unpublished studies. AD: Affective disorder; SD: Standard deviation. §

Second outcome measure: extrapyramidal side effects

3.2.2

As known, SGAs extrapyramidal side effects are less than conventional antipsychotics. In this study, as well, EPS-related adverse event rates and their intensity were low in both groups; however, there were differences in the frequency of some EPS associated with SGAs treatment between the two groups.

Incidence of akathisia The akathisia event rate did not differ significantly between the two groups for quetiapine treatment. Based on five articles included in the AD group (n = 961), the event rate was 6.4%; according to six articles in the SCZ group (n = 1095), the incidence of akathisia was 4.8% (p = 0.463). Patients treated with aripiprazole in the AD group (N = 8, n = 1307) showed more akathisia incidence compared with 3.2.2.1


719

720


Kahn et al. [56] Lieberman et al. [57] Lindenmayer et al. [58] Zhong et al. [64]

Bortnick et al. [91]* Cutler et al. [93] Liebowitz et al. [96] McElroy et al. [97] Suppes et al. [100] Weisler et al. [103] Young et al. [104]

Study name

-2.600 -4.250 -5.220 -1.400 -3.510 0.360 -3.800 -2.765 9.320 5.310 11.080 4.900 8.053 0.405

Mean

Lower limit -8.935 -7.308 -8.261 -4.768 -9.460 -1.861 -6.896 -4.604 6.283 1.200 7.745 -0.184 5.197 -1.141

Standard error 3.232 1.560 1.552 1.718 3.036 1.133 1.580 0.938 1.549 2.097 1.702 2.594 1.457 0.789

Statistics for each study

3.735 -1.192 -2.179 1.968 2.440 2.581 -0.704 -0.927 12.357 9.420 14.415 9.984 10.909 1.951

Upper limit

-15.00

Decreased Cholestrol level

-7.50

0.00

7.50 Increased Cholestrol level

Mean and 95% CI

15.00

AD: Affective disorder; CI: Confidence interval; DT: Diagnostic type; SCZ: Schizophrenia patients.

Figure 3. Forest plot of the effect size estimates of cholesterol changes (mg/dl) in schizophrenia compared with affective disorder patients (p = 0.000) by quetiapine treatment. In Bortnick et al. [91]*, the data were available online in 2010, but the paper was published in 2011.

AD AD AD AD AD AD AD AD SCZ SCZ SCZ SCZ SCZ Overall

Group by DT



Bortnick et al. [91]* Cutler et al. [93] Liebowitz et al. [96] McElroy et al. [97] Suppes et al. [100] Weisler et al. [103] Young et al. [104]

AD AD AD AD AD AD AD AD SCZ SCZ SCZ SCZ Overall


-2.800 -4.400 -3.430 -2.800 -4.680 0.600 -3.600 -2.762 5.670 6.930 -0.390 5.008 -1.016

M ean 2.657 1.434 1.268 1.517 2.495 1.041 1.407 0.843 1.272 1.365 2.911 1.566 0.743

S ta n d a rd e rro r -8.008 -7.210 -5.916 -5.773 -9.570 -1.440 -6.358 -4.415 3.177 4.254 -6.095 1.938 -2.471

Lower lim it 2.408 -1.590 -0.944 0.173 0.210 2.640 -0.842 -1.109 8.163 9.606 5.315 8.078 0.440

U pper lim it

S ta tis tic s fo r e a c h s tu d y

-1 5 .0 0

D e c re a s e d L DL le v e l

-7 .5 0

0 .0 0

7 .5 0 In c re a s e d L DL le v e l

M ean and 95% C I

1 5 .0 0


Figure 4. Forest plot of the effect size estimates of LDL changes (mg/dl) in schizophrenia compared with affective disorder patients (p = 0.000) by quetiapine treatment. In Bortnick et al. [91]*, the data were available online in 2010, but the paper was published in 2011.

Kahn et al. [56] Lindenmayer et al. [58] Peuskens et al. [59]

S tu d y n a m e

G ro u p b y DT



721

722


Chrzanowski et al. [65] Cutler et al. [66] Kane et al. [67] Kane et al. [68] Kasper et al. [69] Kerwin et al. [70] McQuade et al. [72] Pigott et al. [73]

CN138-096 [105]‡ CN138-146[106]‡ El Mallakh et al. [107] Keck et al. [109] Keck et al. [108] Sachs et al. [111] Vieta et al. [112] Young et al. [113]

Study name Upper limit 0.345 0.280 0.169 0.178 0.147 0.250 0.171 0.172 0.197 0.113 0.047 0.085 0.131 0.153 0.037 0.109 0.133 0.088 0.141

Lower limit 0.215 0.161 0.090 0.066 0.027 0.121 0.075 0.074 0.107 0.021 0.010 0.018 0.063 0.108 0.005 0.031 0.045 0.032 0.083

Event rate 0.275 0.214 0.124 0.110 0.065 0.176 0.114 0.114 0.146 0.050 0.022 0.039 0.091 0.129 0.014 0.059 0.078 0.054 0.108

Statistics for each study

Less

-0.25

More

0.25

Akathisia Incidence

0.00

Event rate and 95% CI

0.50


Figure 5. Forest plot of the effect size estimates of akathisia incidence in schizophrenia compared with affective disorder patients (p = 0.001) by aripiprazole treatment. CN138-096z and CN138-146z are unpublished studies.

AD AD AD AD AD AD AD AD AD SCZ SCZ SCZ SCZ SCZ SCZ SCZ SCZ SCZ Overall

Group by DT




Table 3. Summary of the findings presented in the meta-analysis. Metabolic parameters & EPS

Comparison between AD and SCZ groups

LDL mean change (mg/dl) Cholesterol mean change (mg/dl) Akathisia incidence Akathisia incidence Parkinsonism incidence

AD AD AD AD AD

< < > > >

SCZ SCZ SCZ SCZ SCZ

Difference

Medication

Significant (p = 0.000) Significant (p = 0.000) Significant (p = 0.001) Close to be significant (p = 0.065) Close to be significant (p = 0.069)

Quetiapine Quetiapine Aripiprazole Ziprasidone Aripiprazole


In this table, significant side effect differences are shown between AD and SCZ groups. AD: Affective disorder; EPS: Extrapyramidal symptoms; LDL: Low-density lipoprotein; SCZ: Schizophrenia.

SCZ patients (N = 8, n = 2264), 14.6 versus 5.4% respectively. This difference was significant (p = 0.001). Details are shown in Figure 5. For ziprasidone treatment, 10 studies (n = 1459), 4 studies (n = 584) in the AD and 6 studies (n = 875) in the SCZ group, were checked. Akathisia incidence was higher in the AD group compared with the SCZ group, 13.2 versus 7.7%, respectively; this difference is close to be significant (p = 0.065). For risperidone treatment not enough data were available to conduct any comparison between the two groups, in the incidence of akathisia. Incidence of parkinsonism The incidence of parkinsonism did not differ significantly between the two groups for quetiapine treatment. Based on 11 articles included in the AD group (n = 3134), the event rate was 7.5%; according to 8 articles in the SCZ group (n = 1870), the incidence of akathisia was 9.6% (p = 0.326). For aripiprazole treatment, four studies (n = 701) in the AD and seven studies (n = 1979) in the SCZ group were checked. Parkinsonism incidence was higher in the AD group compared with the SCZ group, 10.4 versus 6.7%, respectively; this difference is close to be significant (p = 0.069). The incidence of parkinsonism was not significantly different between the two groups of patients with risperidone treatment. Based on two articles included in the AD group (n = 300), and seven articles in the SCZ group (n = 1194), the event rate was 23.4 versus 29.3%, respectively (p = 0.4). In ziprasidone treatment, the difference in incidence of parkinsonism was not significant between the SCZ (N = 6, n = 868) and the AD groups (N = 3, n = 444). The event rate was 7.5 versus 14.5%, for SCZ and AD, respectively (p = 0.209). 3.2.2.2

Antiparkinson medication use Quetiapine treatment was not associated with significant difference in the use of antiparkinson medication between the two groups. According to 4 articles included in the AD group (n = 489), the event rate was 5.1%; in 10 articles in the SCZ group (n = 2146), the use of such medication was 7.7% (p = 0.455). In aripiprazole treatment, there was no significant difference in the use of antiparkinson medication between the SCZ 3.2.2.3

(N = 6, n = 1958) and the AD groups (N = 4, n = 603). The event rate was 16.7 versus 17.4% for SCZ and AD groups, respectively (p = 0.905). Antiparkinson medication use differed between the two groups for risperidone treatment. SCZ patients (N = 8, n = 1097) used less antiparkinson medication compared with AD patients’ group (N = 2, n = 280), 23.1 versus 28.3%, respectively. However, this difference was not significant (p = 0.575). In ziprasidone treatment, there was no significant difference in the use of antiparkinson medication between SCZ (N = 7, n = 1093) and AD groups (N = 2, n = 317). The event rate was 21.1 versus 35.3%, for SCZ and AD, respectively (p = 0.227). Table 3 presents the summery of the side effect differences found in the meta-analysis between the two diagnostic groups (SCZ and AD). Heterogeneity Heterogeneity of all outcomes (metabolic and extrapyramidal) were explored by I2 statistic; they were all heterogeneous (I2 > 50%). Subanalyses were assessed to determine possible sources of heterogeneity in the results. 3.2.3

3.3

Subanalyses Age

3.3.1

All studies reported mean age and SD of participants; no difference was observed between the two groups of patients in all four treatment groups. Tables 1 and 2 show more information on demographic characteristics among studies included in the meta-analysis. Sex ratio Number of male and female patients was also reported in all studies. Significantly, more males participated in the studies of SCZ group studies compared with the AD groups in all treatment groups, except for risperidone treatment group. Considering the significant difference in male percentage between SCZ and AD patients’ groups, this variable was included in the statistical analysis as a regressor. When the authors performed meta-regression analyses to find the source of heterogeneity in quetiapine treatment, they found that 3.3.2


723


the male percentage of AD patients’ group could be a significant moderator in explaining the heterogeneity of LDL and cholesterol. In the SCZ group, no meaningful regression could be done due to small number of studies; however, because of the significant difference on the sex ratio between AD and SCZ, the sex ratio could be a source of heterogeneity. By performing a meta-regression on akathisia incidence in aripiprazole treatment, the percentage of male gender was not a significant moderator to explain the heterogeneity in AD and SCZ patients’ groups. Dose Based on studies in AD and SCZ groups which specified mean daily dose, no difference was observed between the two groups in all four treatment types. More information on daily dose among studies included in the meta-analysis in each group of disorder is shown in Tables 1 and 2.


3.3.3

Treatment duration The authors stratified the studies based on treatment duration. The results of short-term studies (between 3 and 12 weeks) for quetiapine treatment remained the same as the main analysis. It means increases in cholesterol and LDL levels stayed significantly higher for SCZ patients compared with AD patient in short-term studies. In addition, akathisia incidence was considerably higher in the AD group compared with the SCZ group. The other parameters continued to display no significant difference, similar to the results of the main analysis. In aripiprazole treatment, stratification of studies by treatment duration, showed significantly more akathisia and parkinsonism incidence in AD group compared with SCZ. It should be noted that parkinsonism incidence was not significantly different before stratification. For risperidone and ziprasidone treatment, all parameters displayed no significant difference, as in the main analysis. For studies more than 12 weeks, the authors did not find enough data to check in the AD group in all treatment types. 3.3.4

4.

Discussion

In this article, the authors wanted to make a case that there is some evidence that patients with SCZ and ADs may not experience the same burden of metabolic side effects with any given antipsychotic medication. They decided to study this through a systematic literature review and meta-analysis. They compared the metabolic and extrapyramidal side effects of individual SGAs between two major diagnostic groups, SCZ and AD patients. Based on their hypothesis, there is a difference between SCZ and AD patients for metabolic and extrapyramidal side effects. As in the previous article on olanzapine-induced side effects [45], the authors examined the metabolic side effects (weight gain, blood glucose, cholesterol, LDL and triglyceride levels) of the other four most commonly prescribed SGAs -- quetiapine, ziprasidone, aripiprazole and 724

risperidone -- as the first outcome. The reason for choosing these atypical antipsychotics is their frequent use in the treatment of severe mental illnesses. It is important to mention that the authors did not include olanzapine results in details in this manuscript because their first meta-analysis comparing the potential difference in olanzapine-induced side effects between SCZ and AD patients is already published but they have consolidated its findings in this section [45]. In the prior meta-analysis [45], olanzapine induced significantly more weight gain in SCZ patients compared with the AD group. Based on the present meta-analysis, with aripiprazole treatment, AD patients gained weight and SCZ patients lost weight. In quetiapine treatment, SCZ patients gained more weight; however, the difference was not significant. The authors also examined the mean changes in glucose levels for quetiapine and aripiprazole. Even though there were increases of glucose levels from baseline for these two SGAs, the difference between AD and SCZ was not significant. This outcome was similar to olanzapine-induced glucose changes [45]. The last metabolic factor the authors looked at was mean variations in lipid parameters. Lipid profile in the metaanalysis showed that quetiapine increased significantly the mean level of total cholesterol and LDL in the SCZ group. Quetiapine contributed to more triglyceride increases for SCZ patients compared with the AD group; however, this difference was not significant. It is noteworthy that based on the results reported by Zhornitsky et al. [122], quetiapine may associate with more LDL and cholesterol changes in the SCZ group compared with other mental disorders, which is in agreement with the authors’ findings. In this systematic review [122], quetiapine efficacy and tolerability profiles across psychotic disorders were evaluated. The findings suggest a possible interaction between SCZ genes and quetiapine treatment in increasing metabolic disturbances. Aripiprazole treatment decreased the cholesterol levels in SCZ patients, and was associated with a small increase in cholesterol levels for AD group, a group difference which is also not statistically significant. Due to lack of available data, the levels of triglyceride and LDL for aripiprazole treatment could not be evaluated. As mentioned in the prior article [45], olanzapine treatment increased blood cholesterol and triglycerides levels in both groups and induced more changes in SCZ patients compared with AD patients. However, the differences between two patients groups were not significant, for both blood cholesterol and triglycerides levels. The biological mechanism underlying different metabolic disturbances between SCZ and AD patients in SGAs treatment is not yet clear. Some authors have indicated possible inherent genetic vulnerability to metabolic irregularity in SCZ patients [123-125]. They believe that SCZ may be an independent and important risk factor for both diabetes and impaired glucose tolerance; although, some other studies are not in line with this suggestion [126,127]. Other studies have described that




stress, particularly dysfunction of the hypothalamo-pituitaryadrenal axis (HPA) activity and therefore increases in cortisol and DHEA (dehydroepiandrosterone) levels, in both acute phases of chronic SCZ and bipolar disorder patients may disturb metabolic parameters [128,129]. In some reports, schizophrenic patients showed more sensitivity to daily stress than BP [130]. In addition, the polymorphism of brain-derived neurotrophic factor gene (BDNF) was recently found to be associated with antipsychotic-induced weight gain in patients with chronic SCZ [131]. Furthermore, the duration of treatment or prior antipsychotic medication might influence the metabolic results. BP patients have a better psychosocial functioning profile, and most of them take less antipsychotic medications compared with SCZ patients. Sedentary lifestyle, poor diet, smoking and drug abuse and finally antipsychotic treatment are all important factors which may affect weight gain and other metabolic parameters in schizophrenic patients. Putting all these findings together may help to conclude that the patients with SCZ might be more prone to obesity and other metabolic disturbances compared with other mental disorders. As the second outcome, the authors examined EPS related to SGAs treatment for different mental illnesses. Based on the results, akathisia occurred more frequently in the AD group versus SCZ group in relation to quetiapine, ziprasidone and aripiprazole treatment. However, this difference in akathisia incidence was significant only with aripiprazole treatment. As per the authors’ results, incidence of parkinsonism was higher in the AD group compared with the SCZ group for ziprasidone and aripiprazole treatment; however, the differences between the two disorders were not statistically significant. Antiparkinson medication use was also checked and no significant difference was found between SCZ and AD. However, in the AD group, antiparkinson medication was used more often when the patients were under ziprasidone and aripiprazole treatment. Although some reports in the literature suggest that bipolar disorder patients are more likely to develop EPS than SCZ patients [35,36], the results of the pooled analysis reported by Cavazzoni et al. [27] showed that these findings may be representative of treatment with haloperidol, but not necessarily of olanzapine treatment. Their finding on parkinsonism incidence with olanzapine treatment is consistent with the results in the prior meta-analysis [45], in which parkinsonism incidence was more frequent in SCZ patients than those with bipolar disorders. In a review, Gao et al. [35] indicated that BP, especially in the depression phase, experienced more akathisia, parkinsonism and use of antiparkinson medication compared with those with SCZ, when taking antipsychotics. They mentioned that each atypical antipsychotic has a different liability, and based on their review, haloperidol, aripiprazole, risperidone and ziprasidone treatments were associated with more overall EPS in BP compared with the SCZ group.

The authors performed meta-regression to find the source of heterogeneity in aripiprazole treatment. Akathisia incidence showed no relationship with the male percentage in AD patients. So, male percentage was not a significant moderator to explain the heterogeneity. Furthermore, as mentioned earlier, when the studies were stratified based on treatment duration, in studies less than 12 weeks, significantly more akathisia incidence was observed in the AD patients compared with the SCZ group in aripiprazole and quetiapine treatments. Some limitations affect this meta-analysis, which may confound the authors’ results and may explain the heterogeneity detected in the analysis. In particular, relatively few studies were available for direct comparison of SGAs side effects among AD versus SCZ patients. Therefore, the authors obtained data from articles focusing on either SCZ or AD patients and then compared the results of both groups. To cope with this limitation, prospective controlled trials will be required to compare ADs and SCZ patients directly. It is important to mention that the AD group in this meta-analysis seems a heterogeneous group and as mentioned in Table 2, in AD group, the authors have diverse disorders. However to date, the authors wanted to begin with a more global approach considering only SCZ versus AD which in their examination involved mainly bipolar disorder. In the future, it is necessary breaking down the included studies into major common categories such as mania, bipolar depression and major depression disorder, bipolar I or II, then examine and comment on how this might have influenced the findings. In addition, there was no placebo-control group in the comparison, which may restrict the interpretation of the results. In this study, however, the authors did not compare each side effect of SGAs with placebo because of the low number of placebo-control trials in the included studies for certain atypical antipsychotics. Second, in the present study, the authors tried to capture the major side effects and examined some of the above-mentioned side effects and compared them among different psychiatric conditions. It would also be useful to examine other potential side effects of SGAs such as sexual side effects, somnolence, QTc interval, increased risk of stroke/cerebrovascular accident and increased risk of venous thromboembolism. The review of other side effects will be made in another study since the data are less homogenous based on the current literature. Third, due to the retrospective nature of this analysis, information on severity of psychiatric illnesses could not be included in this analysis. Forth, the authors surveyed the literature until 2010; however, it is clear that after doing their meta-analysis, new studies in this subject have become available, which are not included in this meta-analysis. Another limitation of this meta-analysis is unavailability of data for depot administration of SGAs; in this study only oral monotherapy of SGAs was included.


725



In addition, the authors pooled rates from individual studies to calculate ‘event rates’ and then offered betweengroup (SCZ vs AD) comparison for individual antipsychotic drug. Because of heterogeneity of studies (specially in AD group), pooling of event rates for comparisons could be potentially quite misleading. Incident rates of side effects in individual studies are compared against placebo. They may need to be adjusted against the placebo incident rates before being pooled. Finally, the authors did not examine the impact of previous exposure to antipsychotic treatments, race/ethnicity and initial weight in both groups, which may impact the generalizability of the findings. These variables should be more deeply considered in future studies. Based on the details on daily doses for individual antipsychotics (Tables 1 and 2), the authors did not find significant differences between diagnostic groups. So, they couldn’t conclude that different doses in SCZ and AD groups were responsible for metabolic disturbances in LDL and total cholesterol by quetiapine treatment. Simon et al. [132] provided a review on possible dose--effect relationship with regards to metabolic side effects of antipsychotic medications. They noted that preliminary findings suggest a dose--response metabolic liability for olanzapine with limited data for quetiapine. In the two meta-analyses, the authors did not find significant differences between two diagnostic groups for each SGA. One possibility for finding no difference between diagnostics in this study (the mean dosage for quetiapine is 362 mg for the AD group compared with 495 mg for the SCZ group) could be a consequence of fixed trial protocols used in Phase III studies. In another study [122], the authors aimed to explain the dose--response and comparative efficacy and tolerability of quetiapine across psychiatric disorders. The systematic review showed that in unipolar and bipolar depression, quetiapine was effective versus placebo, at doses of approximately 150 -- 300 and 300 -- 600 mg/day, respectively. In bipolar mania, studies consistently found quetiapine to be effective at doses of approximately 600 mg/day, and in acute SCZ, the majority of studies found quetiapine to be effective at doses of approximately 600 mg/day. In this study, a dosedependent elevation was observed for weight and triglycerides in both SCZ and non-SCZ patients [122]. However, elevations of LDL and total cholesterol were observed uniquely for SCZ patients. Because in this meta-analysis, major depression were very few compared with bipolar disorder and the authors examined them in one diagnostic category as AD group, they may have skewed the findings about quetiapine without a noticeable between-diagnostic-groups difference in the dose. In clinical practice, generally lower doses of antipsychotic medications are used in major depression and bipolar depression and this may influence certain side effects. As with quetiapine, olanzapine is generally used in lower doses in ADs than in SCZ. Studies of quetiapine on patients with major depression have used lower doses than in patients with bipolar disorder. 726

At the end of this discussion, the authors suggest that the between-diagnostic-group differences on certain side effects do not have any crucial implications on the relative risk between different antipsychotic medications. A definitive conclusion about the relative risk of metabolic or extrapyramidal side effects according to phenotype might be premature in the present examination. 5.

Conclusion

Recently, atypical antipsychotic agents have been linked to several forms of morbidity, including obesity, hyperlipidemia and type 2 diabetes mellitus, which predict metabolic syndrome, cardiovascular morbidity and malignancy [25,133,134]. Metabolic syndrome is a significant public health problem in patients with severe mental illnesses and particularly SCZ. The mechanisms responsible for an association between mental disorder, antipsychotic treatment and metabolic syndrome remain elusive [46,47,135]. According to different phenotypes of these mental illnesses and frequent use of SGAs to treat them, studying the degree of sensitivity and tolerability of SGAs in AD and SCZ patients seems essential. In Table 3, the summery of the side effect differences found in this meta-analysis between the two diagnostic groups (SCZ and AD) are shown. In conclusion, side effects are important to consider for prescribers, because the efficacy of treatment may be reduced due to the presence of certain side effects. In general, as many studies have indicated, atypical antipsychotics do not form a homogenous group causing similar adverse events; therefore, some SGAs can lead to metabolic disturbances, while the others may not [2,35,132,136]. The results of the meta-analysis suggest that SCZ patients may be more vulnerable to some SGAs-induced metabolic side effects. Obviously, these findings need further investigation and the variable confounders are still to be clarified. Considering the fact that very little significant between-group (diagnostic) differences were found for individual antipsychotics, the authors state that current data do not justify using a particular antipsychotic medication preferentially based on diagnosis to minimize certain potential side effects. This meta-analysis proposes that factors such as life style and disease phenotype may contribute to this susceptibility in the SCZ group. As mentioned previously in a review article, structural and functional variations in the genome cause proteomic and metabolomic imperfections associated with the disease phenotype [137]. Genetic polymorphism may be an important factor that contributes to metabolic side effects of SGAs between SCZ and AD patients. In addition to a genetic predisposition for metabolic syndromes among schizophrenic patients, lifestyle risk factors such as stress, poor diet, lack of exercise and smoking are more common in schizophrenic patients [138,139]. Patients with severe mental illnesses need to be informed of the different side effects induced by SGAs therapy and they should be monitored regularly, especially for metabolic issues.




In several domains, the results suggest that metabolic side effects are lower in AD than in SCZ or that extrapyramidal side effects are higher in AD patients compared with the SCZ group. However, what that means for a patient and how it changes the follow-up, is a work in progress. In order to achieve a mature discipline of pharmacogenomics of SCZ and bipolar disorder it would be relevant to promote the education of prescribers and the public for the use of genomic screening in clinical practice; pharmacogenomic protocols need to be validated according to drug category and phenotype in order to optimize efficiency. Conducting studies on long-term safety of antipsychotic Bibliography

2.

3.

..

Lublin H, Haug HJ, Koponen H, et al. Ziprasidone versus olanzapine, risperidone or quetiapine in patients chronic schizophrenia: a 12-week open-label, multicentre clinical trial. World J Biol Psychiatry 2009;10(4 Pt 3):710-18 Rummel-Kluge C, Komossa K, Schwarz S, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr Res 2010;123(2-3):225-33 Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 2005;66(1):111-21 Number of patients: 107.

4.

Tohen M, Vieta E. Antipsychotic agents in the treatment of bipolar mania. Bipolar Disord 2009;11(Suppl 2):45-54

5.

Chen J, Gao K, Kemp DE. Second-generation antipsychotics in major depressive disorder: update and clinical perspective. Curr Opin Psychiatry 2011;24(1):10-17

6.

7.

Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord 2010;12(2):116-41 Komossa K, Depping AM, Gaudchau A, et al. Second-generation antipsychotics

Declaration of interest E Stip is holder of Eli Lilly chair of schizophrenia from the Universite´ de Montreál.

for major depressive disorder and dysthymia. Cochrane Database Syst Rev 2010(12):CD008121

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

drugs should be considered a priority in psychopharmacology, as treatment with antipsychotics is often continued for a long period of time or even for the patients’ whole life. Side-effect examination of other antipsychotics, such as asenapine and lurasidone, among different diagnostic groups should be performed in the future when sufficient data are available.

8.

Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009;373(9657):31-41

9.

Holt RI, Abdelrahman T, Hirsch M, et al. The prevalence of undiagnosed metabolic abnormalities in people with serious mental illness. J Psychopharmacol 2010;24(6):867-73

10.

Bellivier F. Schizophrenia, antipsychotics and diabetes: genetic aspects. Eur Psychiatry 2005;20(Suppl 4):S335-9

11.

Gough SC, O’Donovan MC. Clustering of metabolic comorbidity in schizophrenia: a genetic contribution? J Psychopharmacol 2005;19(6 Suppl):47-55

12.

Hasnain M, Vieweg WV, Fredrickson SK, et al. Clinical monitoring and management of the metabolic syndrome in patients receiving atypical antipsychotic medications. Prim Care Diabetes 2009;3(1):5-15

13.

14.

15.

16.

Meyer JM, Stahl SM. The metabolic syndrome and schizophrenia. Acta Psychiatr Scand 2009;119(1):4-14 Phelan M, Stradins L, Morrison S. Physical health of people with severe mental illness. BMJ 2001;322(7284):443-4 Green AI, Drake RE, Brunette MF, Noordsy DL. Schizophrenia and co-occurring substance use disorder. Am J Psychiatry 2007;164(3):402-8 Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area


(ECA) Study. JAMA 1990;264(19):2511-18 17.

Chacon F, Mora F, Gervas-Rios A, Gilaberte I. Efficacy of lifestyle interventions in physical health management of patients with severe mental illness. Ann Gen Psychiatry 2011;10:22

18.

Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics : differential risk and clinical implications. CNS Drugs 2007;21(11):911-36

19.

Stahl SM, Mignon L, Meyer JM. Which comes first: atypical antipsychotic treatment or cardiometabolic risk? Acta Psychiatr Scand 2009;119(3):171-9

20.

De Hert M, Cohen D, Bobes J, et al. Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry 2011;10(2):138-51

21.

De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2011;8(2):114-26

22.

Haddad P. Weight change with atypical antipsychotics in the treatment of schizophrenia. J Psychopharmacol 2005;19(6 Suppl):16-27

23.

Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;19(Suppl 1):1-93

24.

Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156(11):1686-96

25.

De Hert M, Dobbelaere M, Sheridan EM, et al. Metabolic and

727



endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systematic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry 2011;26(3):144-58

35.

Gao K, Kemp DE, Ganocy SJ, et al. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review. J Clin Psychopharmacol 2008;28(2):203-9

26.

Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. Can J Psychiatry 2006;51(8):480-91

36.

27.

Cavazzoni PA, Berg PH, Kryzhanovskaya LA, et al. Comparison of treatment-emergent extrapyramidal symptoms in patients with bipolar mania or schizophrenia during olanzapine clinical trials. J Clin Psychiatry 2006;67(1):107-13

Nasrallah HA, Churchill CM, Hamdan-Allan GA. Higher frequency of neuroleptic-induced dystonia in mania than in schizophrenia. Am J Psychiatry 1988;145(11):1455-6

37.

McDonald C, Bullmore ET, Sham PC, et al. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004;61(10):974-84

38.

Muir WJ, Thomson ML, McKeon P, et al. Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. Am J Med Genet 2001;105(2):152-8

28.

Balestrieri M, Vampini C, Bellantuono C. Efficacy and safety of novel antipsychotics: a critical review. Hum Psychopharmacol 2000;15(7):499-512

29.

Leucht S, Arbter D, Engel RR, et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 2009;14(4):429-47

30.

Miller CH, Mohr F, Umbricht D, et al. The prevalence of acute extrapyramidal signs and symptoms in patients treated with clozapine, risperidone, and conventional antipsychotics. J Clin Psychiatry 1998;59(2):69-75

31.

Kane JM, Fleischhacker WW, Hansen L, et al. Akathisia: an updated review focusing on second-generation antipsychotics. J Clin Psychiatry 2009;70(5):627-43

32.

Kane JM. Tardive dyskinesia rates with atypical antipsychotics in adults: prevalence and incidence. J Clin Psychiatry 2004;65(Suppl 9):16-20

33.

34.

728

Muscettola G, Barbato G, Pampallona S, et al. Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. J Clin Psychopharmacol 1999;19(3):203-8 Tenback DE, van Harten PN, Slooff CJ, van Os J. Evidence that early extrapyramidal symptoms predict later tardive dyskinesia: a prospective analysis of 10,000 patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) study. Am J Psychiatry 2006;163(8):1438-40

39.

40.

41.

42.

43.

44.

Murray RM, Sham P, Van Os J, et al. A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophr Res 2004;71(2-3):405-16 Huang J, Perlis RH, Lee PH, et al. Cross-disorder genome-wide analysis of schizophrenia, bipolar disorder, and depression. Am J Psychiatry 2010;167(10):1254-63 Park N, Juo SH, Cheng R, et al. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia. Mol Psychiatry 2004;9(12):1091-9 Peerbooms OL, van Os J, Drukker M, et al. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: Evidence for a common genetic vulnerability? Brain Behav Immun 2011;25(8):1530-43 Epub 2010. Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460(7256):748-52 van Winkel R, van Os J, Celic I, et al. Psychiatric diagnosis as an independent risk factor for metabolic disturbances: results from a comprehensive, naturalistic screening program. J Clin Psychiatry 2008;69(8):1319-27


45.

Moteshafi H, Zhornitsky S, Brunelle S, Stip E. Comparing tolerability of olanzapine in schizophrenia and affective disorders: a meta-analysis. Drug Safety 2012; In press

46.

Stip E, Lungu OV, Anselmo K, et al. Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment. Transl Psychiatry 2012;2:e128

47.

Lungu O, Anselmo K, Letourneau G, et al. Neuronal correlates of appetite regulation in patients with schizophrenia: Is there a basis for future appetite dysfunction? Eur Psychiatry 2012. In Press, Corrected Proof.

48.

Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive meta-analysis [Computer software version 2.2.057]. 2.2.057 ed. Biostat, Englewood; NJ: 2010

49.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7(3):177-88

50.

Arvanitis LA, Miller BG. Multiple fixed doses of "Seroquel" (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry 1997;42(4):233-46 Number of patients: 258.

..

51.

Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. J Clin Psychiatry 2003;64(5):598-604

52.

Borison RL, Arvanitis LA, Miller BG. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group. J Clin Psychopharmacol 1996;16(2):158-69

53.

Buckley PF, Goldstein JM, Emsley RA. Efficacy and tolerability of quetiapine in poorly responsive, chronic schizophrenia. Schizophr Res 2004;66(2-3):143-50

54.

Conley RR, Kelly DL, Nelson MW, et al. Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Clin Neuropharmacol 2005;28(4):163-8 In this study, the number of patients for the risperidone treatment was 124.

..

55.

Copolov DL, Link CG, Kowalcyk B. A multicentre, double-blind, randomized


..

56.

..


57.

..

58.

..

59.

60.

61.

..

62.

comparison of quetiapine (ICI 204,636, ‘Seroquel’) and haloperidol in schizophrenia. Psychol Med 2000;30(1):95-105 Number of patients: 221. Kahn RS, Schulz SC, Palazov VD, et al. Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2007;68(6):832-42 Number of patients: 458. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-23 Number of patients for quetiapine, ziprasidone, and risperidone treatment groups were 337, 185 and 161, respectively. Lindenmayer JP, Brown D, Liu S, et al. The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study. Psychopharmacol Bull 2008;41(3):11-35 Number of patients: 420. Peuskens J, Trivedi J, Malyarov S, et al. Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients. Psychiatry (Edgmont) 2007;4(11):34-50 Riedel M, Muller N, Spellmann I, et al. Efficacy of olanzapine versus quetiapine on cognitive dysfunctions in patients with an acute episode of schizophrenia. Eur Arch Psychiatry Clin Neurosci 2007;257(7):402-12 Riedel M, Muller N, Strassnig M, et al. Quetiapine has equivalent efficacy and superior tolerability to risperidone in the treatment of schizophrenia with predominantly negative symptoms. Eur Arch Psychiatry Clin Neurosci 2005;255(6):432-7 Number of patients for the risperidone treatment was 140. Sirota P, Pannet I, Koren A, Tchernichovsky E. Quetiapine versus olanzapine for the treatment of negative symptoms in patients with schizophrenia. Hum Psychopharmacol 2006;21(4):227-34

63.

..

64.

..

65.

..

66.

..

67.

..

68.

..

69.

..

70.

Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group. Arch Gen Psychiatry 1997;54(6):549-57 Number of patients: 190. Zhong KX, Sweitzer DE, Hamer RM, Lieberman JA. Comparison of quetiapine and risperidone in the treatment of schizophrenia: a randomized, double-blind, flexible-dose, 8-week study. J Clin Psychiatry 2006;67(7):1093-103 In this study, the number of patients for the quetiapine treatment was 338. Chrzanowski WK, Marcus RN, Torbeyns A, et al. Effectiveness of long-term aripiprazole therapy in patients with acutely relapsing or chronic, stable schizophrenia: a 52-week, open-label comparison with olanzapine. Psychopharmacology (Berl) 2006;189(2):259-66 Number of patients: 104. Cutler AJ, Marcus RN, Hardy SA, et al. The efficacy and safety of lower doses of aripiprazole for the treatment of patients with acute exacerbation of schizophrenia. CNS Spectr 2006;11(9): 691-702; quiz 19 Number of patients: 279. Kane JM, Meltzer HY, Carson WH Jr, et al. Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin Psychiatry 2007;68(2):213-23 Number of patients:153. Kane JM, Osuntokun O, Kryzhanovskaya LA, et al. A 28-week, randomized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry 2009;70(4):572-81 Number of patients: 285. Kasper S, Lerman MN, McQuade RD, et al. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol 2003;6(4):325-37 Number of patients: 861. Kerwin R, Millet B, Herman E, et al. A multicentre, randomized, naturalistic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic


..

71.

..

72.

..

73.

..

74.

..

75.

..

76.

..

77.

..

78.

patients Schizophrenia Trial of Aripiprazole: (STAR) study. Eur Psychiatry 2007;22(7):433-43 Number of patients: 284. Kolotkin RL, Corey-Lisle PK, Crosby RD, et al. Changes in weight and weight-related quality of life in a multicentre, randomized trial of aripiprazole versus standard of care. Eur Psychiatry 2008;23(8):561-6 Number of patients: 278. McQuade RD, Stock E, Marcus R, et al. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry 2004;65(Suppl 18):47-56 Number of patients: 156. Pigott TA, Carson WH, Saha AR, et al. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26week study. J Clin Psychiatry 2003;64(9):1048-56 Number of patients: 155. Arato M, O’Connor R, Meltzer HY. A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study. Int Clin Psychopharmacol 2002;17(5):207-15 Number of patients: 207. Breier A, Berg PH, Thakore JH, et al. Olanzapine versus ziprasidone: results of a 28-week double-blind study in patients with schizophrenia. Am J Psychiatry 2005;162(10):1879-87 Number of patients: 271. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008;28(2 Suppl 1):S20-8 Number of patients: 149. Hirsch SR, Kissling W, Bauml J, et al. A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia. J Clin Psychiatry 2002;63(6):516-23 The number of patients for this article was 148. Kane JM, Khanna S, Rajadhyaksha S, Giller E. Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia.

729



..

India: a randomized, double-blind, controlled, prospective study. J Clin Psychiatry 2007;68(11):1793-8

Int Clin Psychopharmacol 2006;21(1):21-8 Number of patients: 152.

79.

e´ OliJP, Spina E, et al. Ziprasidone and amisulpride effectively treat negative symptoms of schizophrenia: results of a 12-week, double-blind study. Int Clin Psychopharmacol 2006;21(3):143-51

88.

Sechter D, Peuskens J, Fleurot O, et al. Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double-blind study. Neuropsychopharmacology 2002;Dec27(6):1071-81

80.

Sacchetti E, Galluzzo A, Valsecchi P, et al. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr Res 2009;110(1-3):80-9

89.

Yang J, Bahk WM, Cho HS, et al. Efficacy and tolerability of blonanserin in the patients with schizophrenia: a randomized, double-blind, risperidone-compared trial. Clin Neuropharmacol 2010;33(4):169-75 The number of patients for this study was 281.

81.

82.

..

83.

84.

85.

86.

..

87.

730

Azorin JM, Spiegel R, Remington G, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001;Aug158(8):1305-13 Bondolfi G, Dufour H, Patris M, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 1998;155(4):499-504 The number of patients for this study was 336. Dollfus S, Olivier V, Chabot B, et al. Olanzapine versus risperidone in the treatment of post-psychotic depression in schizophrenic patients. Schizophr Res 2005;78(2-3):157-9 Hwang TJ, Lee SM, Sun HJ, et al. Amisulpride versus risperidone in the treatment of schizophrenic patients: a double-blind pilot study in Taiwan. J Formos Med Assoc 2003;102(1):30-6 Lin CH, Kuo CC, Chou LS, et al. A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia. J Clin Psychopharmacol 2010;30(5):518-25 Peuskens J, Bech P, Moller HJ, et al. Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group. Psychiatry Res 1999;88(2):107-17 Number of patients: 277. Saddichha S, Manjunatha N, Ameen S, Akhtar S. Effect of olanzapine, risperidone, and haloperidol treatment on weight and body mass index in first-episode schizophrenia patients in

..

90.

Altamura AC, Salvadori D, Madaro D, et al. Efficacy and tolerability of quetiapine in the treatment of bipolar disorder: preliminary evidence from a 12-month open-label study. J Affect Disord 2003;76(1-3):267-71

91.

Bortnick B, El-Khalili N, Banov M, et al. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: a placebo-controlled, randomized study. J Affect Disord 2011;128(1-2):83-94 Number of patients: 147.

..

92.

..

93.

..

94.

..

95.

Calabrese JR, Keck PE Jr, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005;162(7):1351-60 Number of patients: 342. Cutler AJ, Montgomery SA, Feifel D, et al. Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study. J Clin Psychiatry 2009;70(4):526-39 Number of patients: 294. Endicott J, Paulsson B, Gustafsson U, et al. Quetiapine monotherapy in the treatment of depressive episodes of bipolar I and II disorder: improvements in quality of life and quality of sleep. J Affect Disord 2008;111(2-3):306-19 Number of patients: 698. Langosch JM, Drieling T, Biedermann NC, et al. Efficacy of quetiapine monotherapy in rapid-cycling bipolar disorder in comparison with sodium valproate.


J Clin Psychopharmacol 2008;28(5):555-60 96.

..

Liebowitz M, Lam RW, Lepola U, et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depress Anxiety 2010;27(10):964-76 Number of patients: 387.

97.

McElroy SL, Martens BE, Winstanley EL, et al. Placebo-controlled study of quetiapine monotherapy in ambulatory bipolar spectrum disorder with moderate-to-severe hypomania or mild mania. J Affect Disord 2010;124(1-2):157-63

98.

McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry 2010;71(2):163-74 Number of patients: 461.

..

99.

..

McIntyre RS, Brecher M, Paulsson B, et al. Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol 2005;15(5):573-85 Number of patients: 101.

100. Suppes T, Datto C, Minkwitz M, et al. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. J Affect Disord 2010;121(1-2):106-15 .. Number of patients: 133. 101. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol 2006;26(6):600-9 .. Number of patients: 306. 102. Vieta E, Calabrese JR, Goikolea JM, et al. Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2007;9(4):413-25 103. Weisler R, Joyce M, McGill L, et al. Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind,


..

104.

..


105.

..

106.

..

107.

..

108.

109.

..

110.

randomized, placebo-controlled study. CNS Spectr 2009;14(6):299-313 Number of patients: 522. Young AH, McElroy SL, Bauer M, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 2010;71(2):150-62 Number of patients: 518. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Aripiprazole in the Treatment of Patients With Bipolar I Disorder With a Major Depressive Episode. [ClinicalTrials.gov identifier CN138096*]. BRISTOL-MYERS SQUIBB 2011. Number of patients: 186. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Aripiprazole in the Treatment of Patients With Bipolar I Disorder With a Major Depressive Episode. [ClinicalTrials.gov identifier CN138146*]. BRISTOL-MYERS SQUIBB. 2011. Number of patients: 187. El Mallakh RS, Vieta E, Rollin L, et al. A comparison of two fixed doses of aripiprazole with placebo in acutely relapsed, hospitalized patients with bipolar disorder I (manic or mixed) in subpopulations (CN138-007). Eur Neuropsychopharmacol 2010;20(11):776-83 Number of patients: 267. Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry 2006;67(4):626-37 Keck PE Jr, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003;160(9):1651-8 Number of patients: 130. Kemp DE, Calabrese JR, Tran QV, et al. Metabolic syndrome in patients enrolled in a clinical trial of aripiprazole in the maintenance treatment of bipolar I disorder: a post hoc analysis of a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2010;71(9):1138-44

111.

..

112.

..

113.

..

114.

..

115.

..

116.

..

117.

..

118.

..

119.

Sachs G, Sanchez R, Marcus R, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebocontrolled study. J Psychopharmacol 2006;20(4):536-46 Number of patients: 137. Vieta E, Bourin M, Sanchez R, et al. Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry 2005;187:235-42 Number of patients: 175. Young AH, Oren DA, Lowy A, et al. Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry 2009;194(1):40-8 The number of patients for this study was 167. Keck PE Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry 2003;160(4):741 Number of patients: 131. Keck PE Jr, Versiani M, Warrington L, et al. Long-term safety and efficacy of ziprasidone in subpopulations of patients with bipolar mania. J Clin Psychiatry 2009;70(6):844-51 Number of patients: 127. Potkin SG, Keck PE Jr, Segal S, et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol 2005;25(4):301-10 Number of patients: 139. Vieta E, Ramey T, Keller D, et al. Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study. J Psychopharmacol 2010;24(4):547-58 Number of patients: 178. Hirschfeld RM, Keck PE Jr, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry 2004;161(6):1057-65 Number of patients: 134. Khanna S, Vieta E, Lyons B, et al. Risperidone in the treatment of acute

..

mania: double-blind, placebo-controlled study. Br J Psychiatry 2005;187:229-34 Number of patients: 146.

120. Muller-Siecheneder F, Muller MJ, Hillert A, et al. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. J Clin Psychopharmacol 1998;18(2):111-20 121. Smulevich AB, Khanna S, Eerdekens M, et al. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. Eur Neuropsychopharmacol 2005;15(1):75-84 .. Number of patients: 154. 122. Zhornitsky S, Potvin S, Moteshafi H, et al. Dose-response and comparative efficacy and tolerability of quetiapine across psychiatric disorders: a systematic review of the placebo-controlled monotherapy and add-on trials. Int Clin Psychopharmacol 2011;26(4):183-92 123. Dasgupta A, Singh OP, Rout JK, et al. Insulin resistance and metabolic profile in antipsychotic naive schizophrenia patients. Prog Neuropsychopharmacol Biol Psychiatry 2010;34(7):1202-7 124. Spelman LM, Walsh PI, Sharifi N, et al. Impaired glucose tolerance in first-episode drug-naive patients with schizophrenia. Diabet Med 2007;24(5):481-5 125. Venkatasubramanian G, Chittiprol S, Neelakantachar N, et al. Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. Am J Psychiatry 2007;164(10):1557-60 126. Arranz B, Rosel P, Ramirez N, et al. Insulin resistance and increased leptin concentrations in noncompliant schizophrenia patients but not in antipsychotic-naive first-episode schizophrenia patients. J Clin Psychiatry 2004;65(10):1335-42 127. Zhang ZJ, Yao ZJ, Liu W, et al. Effects of antipsychotics on fat deposition and changes in leptin and insulin levels. Magnetic resonance imaging study of previously untreated people with schizophrenia. Br J Psychiatry 2004;184:58-62 128. Gallagher P, Watson S, Smith MS, et al. Plasma cortisol-dehydroepiandrosterone


731


(DHEA) ratios in schizophrenia and bipolar disorder. Schizophr Res 2007;90(1-3):258-65


129. Steen NE, Lorentzen S, Barrett EA, et al. Sex-specific cortisol levels in bipolar disorder and schizophrenia during mental challenge--relationship to clinical characteristics and medication. Prog Neuropsychopharmacol Biol Psychiatry 2011;35(4):1100-7 130. Myin-Germeys I, Peeters F, Havermans R, et al. Emotional reactivity to daily life stress in psychosis and affective disorder: an experience sampling study. Acta Psychiatr Scand 2003;107(2):124-31 131. Zhang XY, Zhou DF, Wu GY, et al. BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology 2008;33(9):2200-5 132. Simon V, van Winkel R, De Hert M. Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review. J Clin Psychiatry 2009;70(7):1041-50 133. Henderson DC, Cagliero E, Copeland PM, et al. Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents:

732

a frequently sampled intravenous glucose tolerance test and minimal model analysis. Arch Gen Psychiatry 2005;62(1):19-28 134. Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry 2002;59(4):337-45 135. Bond DJ, Kauer-Sant’Anna M, Lam RW, Yatham LN. Weight gain, obesity, and metabolic indices following a first manic episode: prospective 12-month data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM). J Affect Disord 2010;124(1-2):108-17 136. Rummel-Kluge C, Komossa K, Schwarz S, et al. Second-generation antipsychotic drugs and extrapyramidal side effects: a systematic review and meta-analysis of head-to-head comparisons. Schizophr Bull 2012;38(1):167-77. Epub 2010 137. Cacabelos R, Hashimoto R, Takeda M. Pharmacogenomics of antipsychotics efficacy for schizophrenia. Psychiatry Clin Neurosci 2011;65(1):3-19 138. Bai YM, Chen TT, Liou YJ, et al. Association between HTR2C


polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics. Schizophr Res 2011;125(2-3):179-86 139. Liou YJ, Bai YM, Lin E, et al. Gene-gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics. Pharmacogenomics J 2012;12(1):54-61

Affiliation Hoda Moteshafi1,2 & Emmanuel Stip†1,3,4 MD MSc FRCP DPAPA † Author for correspondence 1 De´partement de Pharmacologie, Universite´ de Montreál, Montreál, Que´bec, Canada 2 Centre de recherche Fernand-Seguin, Montreál, Que´bec, Canada 3 De´partement de Psychiatrie, Faculte´ de Me´decine, Universite´ de Montreál, Montreal, Quebec, Canada Tel: +514 343 7755; Fax: +514 343 5785; E-mail: [email protected] 4 CHUM, Montreál, Que´bec, Canada