Do antipsychotics increase diabetes risk in children and adolescents?

Review

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Do antipsychotics increase diabetes risk in children and adolescents? 1.

Introduction

2.

Methods

3.

Results

4.

Moderators of T2DM risk

5.

Conclusion

6.

Expert opinion

Britta Galling & Christoph U Correll† †

Zucker Hillside Hospital, Psychiatry Research, Glen Oaks, NY, USA

Introduction: Glucose dysregulation and type 2 diabetes mellitus (T2DM) are feared antipsychotic drug adverse effects. Despite increasing utilization, data about antipsychotic risk of T2DM in youth are scarce. Areas covered: We conducted a systematic PubMed/MEDLINE search until 15 May 2014 focusing on studies with ‡ 20 youths aged £ 24 years, reporting quantitative data on: i) change in fasting glucose, hemoglobin A1c, insulin or insulin resistance after antipsychotic initiation (studies = 19, n = 2123, age = 13.3 years, follow up = 28.8 weeks); or ii) prevalence (studies = 4) or incidence (studies = 8, follow up = 1.57 years) of T2DM in antipsychotic-exposed youth (studies = 10, n = 65,486, age = 14.2 years) versus healthy controls (studies = 4, n = 246,828), psychiatric controls (studies = 5, n = 61,784) or without control groups (studies = 2). Expert opinion: Antipsychotics are associated with early adverse changes in glucose metabolism that are greater with all analyzable antipsychotics compared to controls, being highest with olanzapine, followed by quetiapine, aripiprazole and risperidone; but data were scarce. Although T2DM is fortunately rare in antipsychotic-treated youth, its prevalence (odds ratio [OR] = 8.176, 95% CI = 7.139 -- 9.362) and incidence (OR = 1.450, 95% CI = 1.101 -- 1.911, p = 0.006) were higher than in healthy controls. Similarly, T2DM prevalence (OR = 3.475, 95% CI = 3.019 -- 4.001, p < 0.0001) and incidence (OR = 5.376, 95% CI = 4.004 -- 7.233, p < 0.0001, excluding one outlying study) were higher than in psychiatric controls. Antipsychotics should only be used after lower-risk interventions failed, and inappropriately low clinical metabolic monitoring must be remedied. Keywords: adolescents, antipsychotics, children, diabetes, glucose, hemoglobin A1c, healthy controls, incidence, insulin, psychiatric controls Expert Opin. Drug Saf. [Early Online]

1.

Introduction

Antipsychotics are among the most prescribed psychotropic medications, being used far beyond their initial indication of psychotic disorders, especially in youth [1-4]. Due to their relatively lower risk for distressing and potentially disabling neuromotor adverse effects than first-generation antipsychotics (FGAs) [5,6], secondgeneration antipsychotics (SGAs) have been used increasingly, including in youths who are more vulnerable to antidopaminergic adverse effects than adults [7]. Although both SGAs and FGAs are heterogeneous regarding their cardiometabolic risk [8-11], most SGAs have a greater propensity than most FGAs for significant body weight gain and metabolic abnormalities [12-16], which start already after a short period of treatment and even at low doses [13,15,17] and which are an established risk factor for type 2 diabetes (T2DM) and cardiovascular illness, causing premature mortality in adults [6,9,13-16]. Impaired glucose tolerance (IGT) and insulin resistance

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1

B. Galling & C. U. Correll

Article highlights. .

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The risk of hyperglycemia and type 2 diabetes mellitus is significantly higher in antipsychotic-treated youths compared to healthy controls. Olanzapine affects glucose homeostasis the most among second-generation antipsychotics. The risk of glucose metabolism dysfunction should be considered when making the decision to start or continue antipsychotic treatment and when selecting among individual agents. Routine and proactive cardiovascular monitoring and management is urgently needed in youths with mental illness, especially for those treated with antipsychotics. Patients and parents should be informed about the potential cardiometabolic adverse effects of antipsychotics and should be supported in counteracting these changes by healthy nutrition and physical activities.

2.

Methods

Literature search We searched PubMed/MEDLINE from database inception until 15 May 2014, using the following search terms without language restrictions: (child* OR adolescent* OR pediatric OR youth) AND (antipsych* OR neuroleptic) AND (‘hemoglobin A1C’ OR HbA1c OR glucose OR hyperglycemia OR diabetes OR prediabetes OR insulin OR hyperinsulinemia). The electronic search was supplemented by a manual review of reference lists from eligible publications and relevant reviews. Whenever data were missing for the review, authors were contacted for additional information. 2.1

This box summarizes key points contained in the article.

that can be precursors of T2DM have been associated with antipsychotic use, with varying degrees of risk across different antipsychotics [8,18-23]. Age-inappropriate body weight gain [13,18,24-27] and worsening of glucose and lipid metabolism [17,26,28] seem to be more pronounced in youths than in adults, although some of the observed alterations may be larger in youths compared to adults due to different baseline values. Thus, youths, who have on average a shorter psychiatric and treatment history may have healthier body weight and blood values at the starting point of antipsychotic treatment. By contrast, in adults who are generally ill for a longer period of time, weight gain and glucose resistance have emerged to a certain degree already, which can make further changes less pronounced [14,15,29,39]. Nevertheless, due to the relatively low incidence of T2DM and usually considerable lag time between antipsychotic treatment and associated early cardiometabolic changes until T2DM development, far less is known about the risk of T2DM in youths exposed to antipsychotics [31,32]. Further, since patient lifestyle behaviors, baseline body mass index (BMI) and genetic risk factors interact with the likelihood of developing T2DM [29], studies that carefully control for such non-medication-related risk factors are needed in order to determine the magnitude of the antipsychotic-related risk. Moreover, as children and adolescents generally have a much shorter antipsychotic exposure history than adults, the absolute risk for developing T2DM might be lower than in adults, and long-term studies are required to detect such potential risk in youths. Although several prior reviews summarized cardiometabolic effects of antipsychotics in youths [7,13-15,27,29], none has quantitatively pooled antipsychotic effects on all glucose metabolism parameters and compared the results in youths treated with antipsychotics with psychiatric and healthy control groups. Thus, since antipsychotics are used in 2

considerable quantities in youths for conditions for which evidence for their efficacy exists [25,33-36] and off label [37-40], and as data on the risk for T2DM in youth are scarce, we conducted a systematic review in order to summarize the extent of changes in blood sugar, hemoglobin A1c (HbA1c), insulin and insulin resistance, and to derive estimates of the prevalence and incidence of T2DM in youths treated with antipsychotics. This analysis was designed to determine the degree of risk and the variation with different antipsychotics, assuming that -- based on the literature -- antipsychotics would be associated with a significantly increased risk for these glucose metabolism-related outcomes compared to healthy controls or psychiatric controls not receiving antipsychotics, and that the risk would vary across different antipsychotics.

Inclusion criteria Included were studies with the following characteristics: i) containing ‡ 20 youths ii) aged £ 24 years, iii) treated with antipsychotics, iv) reporting quantitative data on change in glucose, HbA1c, insulin or insulin resistance, or on the prevalence or incidence of T2DM. 2.2

Outcomes and data abstraction The main outcomes included changes in i) glucose, ii) HbA1c, iii) insulin or iv) insulin resistance, as well as v) prevalence or vi) incidence of T2DM in youths treated with antipsychotics with or without comparison to a control group of youths with or without psychiatric disorders not receiving antipsychotics. Whenever articles reported on overlapping samples, we only included details of the study with the largest sample size but also reported the results of studies with smaller subsamples for trial, patient or treatment characteristics or outcomes that were not included in the report on the largest sample. Galling abstracted all data and Correll checked the data abstraction; any inconsistencies were resolved by consensus. 2.3

Data analysis Frequencies of study, patient and treatment characteristics were analyzed descriptively. Mean changes for individual antipsychotics with data from ‡ 2 studies in fasting glucose, HbA1c, insulin or insulin resistance, expressed as homeostatic 2.4

Expert Opin. Drug Saf. (2014) 14(2)


Do antipsychotics increase diabetes risk in children and adolescents?

model assessment (HOMA-IR) [40], were compared with controls and other antipsychotic using t-test (whenever data were provided by ‡ 2 studies). Prevalence of T2DM was calculated as the number of patients with T2DM as defined by the authors divided by the number of individuals at risk (i.e., individuals free of diagnosis and treatment of T2DM). Incidence of T2DM was computed as the number of patients with new onset T2DM as defined by the authors during the observation period divided by the number of individuals at risk (i.e., individuals free of diagnosis and treatment of T2DM at baseline). Incidence/1000 patients was computed by dividing the number of patients with study-defined T2DM by the number of patients at risk multiplied by 1000. Incidence of abnormal fasting blood sugar (FBS) and T2DM was compared across groups using chi-squared or Fisher’s exact test, as appropriate, expressing differences as odds ratios (ORs). Analyses were conducted using JMP 5.0.1, 1989--2003 (SAS Institute Inc.); all tests were twosided, with a set at 0.05. 3.

Results

Studies reporting on change in glucose or HbA1c Study characteristics

3.1.1

A total of 19 studies (n = 2123) reported on blood sugar changes: 16 (88.9%, n = 1887) had a longitudinal design and 3 (11.1%, n = 236) were cross-sectional (Table 1) [17,25,34,41-56]. Thirteen studies (68.4%) were conducted in the USA, and three studies each (15.8%) were conducted in Canada and in Europe, respectively. The follow-up-duration ranged between 3 weeks and 2 years (mean: 28.8 weeks). The most common outcome variable was change in FBS (studies = 1641) and IGT (FBS ‡ 100 mg/dl, studies = 6, n = 548). An oral glucose tolerance test was used in two studies (n = 78) and two studies reported on change in HbA1c levels (n = 113) (Table 2). Patient and treatment characteristics The age at study inclusion ranged from 4 to 19 years (mean: 13.3, studies = 17, n = 1971). Altogether, 59.2% of patients were male (studies 19, n = 2123) and 62.0% were white (studies = 16, n = 1850). The most common diagnoses were psychosis-spectrum disorders (31.8%), mood disorders (i.e., bipolar disorder: 23.4%; mood disorder not otherwise specified (NOS): 4.3%, depression: 2.9%), pervasive developmental disorder (PDD)/autism (19.2%) and attention-deficit/ 3.1.2

Control groups, type of matching Seven studies compared data with a control group (n = 577), of which three were randomized, placebo-controlled studies (n = 257) that did not use further statistical adjustment (Table 1) [43,44,46]. Two studies had a control group of psychiatric patients who refused or stopped taking an antipsychotic (n = 33) [17,41]. Two other studies used antipsychotic-naı¨ve patients as a psychiatric control group [50,51]. In one of these studies [50], groups were matched for age, sex, ethnicity, BMI standardized for age and sex, pubertal status, degree of psychiatric illness, psychiatric diagnoses and other medications. 3.1.3

Change in fasting glucose and HbA1c FBS increased the most with olanzapine (4 mg/dl, 95% CI: 1.47 to 6.61), clozapine (4.5 mg/dl, only one study) and ziprasidone (3.7 mg/dl, only one study) (Table 2). Lesser and non-significant increases were reported with quetiapine (1.8 mg/dl, 95% CI: -0.06 to 3.66), aripiprazole (1.5 mg/dl, 95% CI: -0.58 to 3.6) and risperidone (0.4 mg/dl, 95% CI: -2.9 to 3.7). FBS changes in patients treated with FGAs were on the lower end (haloperidol: -0.3 mg/dl, molindone: 0.9 mg/dl) (Table 2). FBS changes each individual antipsychotic, for which ‡ 2 studies provided data, were significantly greater than in control subjects (-1.47, 95% CI: -3.99 to 1.01) (Table 3). Among SGAs, olanzapine had significantly greater glucose elevations compared to aripiprazole, quetiapine and risperidone, whereas risperidone had significantly smaller elevations than the other three SGAs, and aripiprazole was associated with less glucose elevation than quetiapine (Table 3). The incidence rate (IR) of impaired fasting glucose (IFG, defined as fasting blood sugar between 110 and 125 mg/dl) in all SGA-treated patients pooled together was 7.5% (38/506, 6 studies) compared to 0% in controls (0/15, 1 study) (p = 0.63). Data were insufficient to compare individual antipsychotics. Data for change in HbA1c were too scarce to provide meaningful data for comparison (Table 3). 3.1.4

The initial search resulted in 582 hits. A total of 499 studies were excluded on the title/abstract level. Of the remaining 83 references, 54 were excluded after full text review (outside of age range: n = 22; study population < 20 patients: n = 10; treatment recommendations: n = 7; duplicate data publication: n = 5; review article: n = 4; lacking glucose metabolism-related outcome measure: n = 4; study including only youths with T2DM: n = 1; methods paper: n = 1), yielding 29 studies that were included in this review. 3.1

hyperactivity disorder (ADHD) and disruptive behavior disorder (DBD) (17.7%) (Table 1). Details regarding antipsychotic treatment were provided in all 19 studies: Most patients were treated with SGAs (aripiprazole: 36.2%, risperidone: 32.2%, olanzapine: 19.3%, quetiapine: 5.9%, ziprasidone: 3.0% and clozapine: 0.8%); only 2.6% of patients received FGAs.

Studies reporting on change in insulin or HOMA-IR 3.2.1 Study characteristics 3.2

Insulin data and HOMA-IR data were reported in six studies (n = 594). Five studies reported changes in fasting insulin (n = 558) with a mean follow-up time of 37.6 weeks (range: 2 -- 18 months). HOMA-IR was reported in three studies (n = 474) and one study also focused on proinsulin, Matsuda index (insulin sensitivity), insulinogenic index (insulin


3

4


LS: Randomized, double- 3w blind, placebo-controlled study of RIS in youth with acute mania in BPD

Haas et al. (2009) (USA) [47]

Ø 12m

4w

111

66

197

202

63

257

101

N*

13.0 (10 -- 17)

15.2 (4 -- 18)

13.5 (13 -- 17)

15.5 (13 -- 17)

13.6 (10 -- 17)

13.9 (4.3 -- 19.9)

11.7 (7 -- 17)

Age, years (range) *

Male: 48.6; Caucasian: 76.6; AA: 17.1; Mixed: 3.6; Other: 2.7

Male: 66.7; White: 89.4; Hispanic/Latin American: 1; AA: 1.5

Male: 54.5; Caucasian: 57.4; AA: 13.9; Asian: 13.9; Other: 14.8 Male: 52.3; Caucasian: 67.5

Male: 67

Male: 58; Caucasian: 49, AA: 24.7; Hispanic: 8.2; Asian: 3.7; Mixed: 11.6

Male: 93; White: 81.2; AA: 12.9; Other: 3.9; Hispanic: 2

Male (%)*; Race (%)* Baseline: RIS: 100 f/u: RIS: 73.3; Other SGA: 8.9; Discontinuation: 17.8

Antipsychotic drug (%)*

Patients refusing or stopping antipsychotics within 4 w (n = 15)

RIS: 100

RIS: Ø N/A (0.5 -- 2.5 mg/d vs 3 -- 6 mg/d)

Placebo (n = 58)

RIS: 3.5 mg/d ± 3.1; OLZ: 9.8 mg/d ± 5.6; QTP: 390.8 ± 321.2

RIS: 33.3, OLZ: 30.3; QTP: 36.4 SCZ/PSY: 51.5 (SCZ: 13.6; SCZphreniform d/o: 13.6; PSY NOS: 18.2; DEP with psychosis: 6.1); BPD: 12.1; ODD: 6.1; ADHD: 6.1; CD: 12.1; PDD: 3; ED: 9.1 BPD: 100

Placebo (n = 99)

Placebo (n = 100)

N/A (10 vs 30 mg/d)

ARI: 19.4 mg/d (10 vs 30 mg/d)

ARI: 100

ARI: 100

Control group Discontinuation of RIS (n = 18)

N/A (3 weeks: 80 or 160 mg/d, then flexible titration)

N/A

0.03 ±0.02 mg/kg/d

Mean dose*

BPD: 100

SCZ: 100

ARI: 16; OLZ: 17.5; SCZ-spectrum d/ QTP: 14; RIS: 52.5 o: 31.5 (psychosis NOS: 20.6; SCZ/SzAD: 10.5); Mood spectrum d/ o: 48.6 (DEP: 17.5; BPD: 15.2; Mood NOS: 13.2); ODD/CD: 15.2; Autism:7.4 BPD: 73, SCZ/SzAD: 27 ZIP: 100

ADHD: 88.1 ; DBD: 88.1; PDD: 18.8; DEP: 4.9; ANX: 30.7; tic d/o: 24.8

Diagnosis (%)*

*Of the SGA-medicated subgroup. AA: African-American/Black; AD: Antidepressant; ADHD: Attention-deficit-hyperactivity disorder; AN: Anorexia nervosa; ANX: Anxiety disorder; AP: Antipsychotics; ARI: Aripiprazole; BPD: Bipolar disorder; CD: Conduct disorder; CLZ: Clozapine; CSS: Cross-sectional study; D: Days; DBD: Disruptive behavior disorder; DEP: Depression; d/o: Disorder; ED: Eating disorder; FGA: First-generation antipsychotic; HAL: Haloperidol; LS: Longitudinal study; m: Months; MD: Mood disorder; MDD: Major depressive disorder; MOL: Molindone; N/A: Not available; NOS: No otherwise specified; ODD: Oppositional defiant disorder; OLZ: Olanzapine; PDD: Pervasive developmental disorder; PSY: Psychosis; QTP: Quetiapine; RIS: Risperidone; SCZ: Schizophrenia; SGA: Second-generation antipsychotic; SzAD: Schizoaffective disorder; w: Weeks; yrs: Years; ZIP: Ziprasidone.

Fraguas et al. 2008 (Spain) [46]

Findling et al. (2009) (USA) [45]

Findling et al. (2008) (USA) [44] 6w

27w

LS: Open-label study on the tolerability of oral ZIP consisting of a 3-week fixed-dose period and a subsequent 24-week flexible-dose period LS: Randomized, doubleblind, placebo-controlled 6w-study of ARI in youths with SCZ LS: Randomized, doubleblind, placebo-controlled 4w-study of ARI in youth with BPD LS: Naturalistic study of metabolic and hormonal side effects due to SGAs on an adolescent unit (2005 -- 2006)

Correll et al. (2009) ( USA) [17]

DelBello et al. (2008) (USA) [43]

Follow up

18m LS: Naturalistic study on youths treated with RIS in different child psychiatry clinics 12w LS: Non-randomized inception cohort study of cardiometabolic effects of first time SGA treatment in youths (2001 -- 2007)

Design and setting

Calarge et al. (2014) (USA) [42]

Study/country

Table 1. Design, demographic and treatment characteristics of studies providing data on glucose metabolism dysfunction in antipsychotic-treated youths.



LS: Retrospective chart review on effects of OLZ and RIS on metabolic factors (inpatient psychiatric hospital, 2003 -- 2005) LS: Database of six studies of OLZ in youths

Design and setting

Ø 0.55 yrs

Ø 26d

Follow up


9.6 (6 -- 17)

12 (6 -- 17)

N/A (9 -- 18)

13.7 ± 2.7

22

36

163

15.8 (10 -- 18)

15.8 (13 -- 17)

13 (6 -- 18)


330

39

179

49

N*

Male: 62

Male: 50; Caucasian: 67


Male: 87; Caucasian: 71.2; AA: 21.2; Other: 7.6

Male: 69.2; Caucasian: 73.3; AA: 11; Asian: 0.6; Hispanic: 8.6; Other: 3.5 Male: 53.8; White: 20.5

Male: 64; AA: 16; Asian: 0; Caucasian: 72; Hispanic: 12

Male (%)*; Race (%)*


RIS: 100

ARI: 100

CLZ: 46.2; OLZ: 53.8

OLZ: 100

PSY d/o: 17; MD: 25; ANX: 12; DBD: 23; PDD: 9; substance abuse d/o: 3

RIS: 35.3; QTP: 41.2; OLZ: 14.7; CLZ: 2.9; SGA-combination: 5.9

RIS: 56; QTP: 44 PSY: 8.3; Depressive d/ o: 27.8; ODD: 8.3; Learning d/o: 2.8; Tic d/o: 8.3; ANX: 5.6; ADHD: 36.1; DBD: 2.8; PDD: 13.9; substance-related d/o: 2.8

PDD: 31.8; early onset SCZ: 45.5; tic d/o: 9.1; DBD: 13.6

Autistic d/o: 100

SCZ: 64.1; SzAD: 35.9

SCZ: 47.7; bipolar mania: 45.3; prodromal to PSY: 7

RIS: 49; OLZ: 51 BPD, mood d/o NOS and MDD: ‘most common’ SzAD; SCZ, SCZphreniform d/o: 16; substance abuse or dependence: 29; ADHD: 18

Diagnosis (%)*

RIS: 1.3 mg/d (0.25 -- 4.0 mg/d); QTP: 132 mg/d (25 -- 600 mg/d); OLZ: 10.4 mg/d (12.5 -- 30 mg/d); CLZ: 88.9 mg/d (12.5 -- 175 mg/d)

N/A

1.23 mg/d (0.24 -- 4 mg/d)

CLZ: 403.1 mg/d (50 -- 700 mg/d); OLZ: 26.2 mg/d (10 -- 30 mg/d) 10.6 mg/d (1.1 -- 15.0 mg/d)

Ø 12.1 mg/d (2.5 -- 20 mg/d)

RIS: 2.6 mg/d (1 -- 7), OLZ: 12.5 mg/d (5 -- 25 mg/d)

Mean dose*

Psychiatric, SGA-naı¨ve (n = 269)

Psychiatric, SGA-naı¨ve (n = 18).

-

-

-

-

-

Control group


12w LS: Open-label, follow-up study: CLZ versus OLZ in refractory early onset SCZ Marcus et al. 12m LS: Open-label safety (2011) and tolerability study (USA) [49] of ARI in autistic d/o in 53 centers in the USA (2006 -- 2009) Margari et al. Ø 6m LS: Prospective observa(2013) tional study of tolerability (3 -- 12) (Italy) [50] of RIS in AP-naı¨ve youths in a child neuropsychiatric unit (2009 -- 2012) Ngai et al. CSS: Glucose homeostasis, (2014) insulin sensitivity, insulin (Canada) [51] secretion, and b-cell function with RIS, QTP in SGA-naı¨ve youths in a child and adolescent psychiatry department (2009 -- 2012) Panagiotopoulos CSS: Retrospective chart et al. (2009) review of all child and (Canada) [52] adolescent psychiatry emergency admissions (2005 -- 2007)

Kumra et al. (2008) (USA) [35]

Kryzhanovskaya et al. (2012) (USA) [26]

Khan et al. (2009) (USA) [48]

Study/country

Table 1. Design, demographic and treatment characteristics of studies providing data on glucose metabolism dysfunction in antipsychotic-treated youths (continued).



5

6

LS: Observational study of patients with eating disorders started on OLZ (2004 -- 2008) CSS: Database study examining the use of SGA in youth with ADHD

16 LS (84.2%, n = 1887); 3 CSS (15.8%, n = 236)

Swenne et al. (2011) (Sweden) [56]

TOTAL n = 19 USA: 13 (68.4%) Canada: 3 (15.8%) Europe: 3 (15.8%)


2123 13. (17 studies, N = 1971)

29.8w (3w -2 years)

12.3 (6 -- 18)

14.4 (£ 18)

N/A (8 -- 19)

14.8 (8 -- 19)

13.1 (4 -- 17)


37

47

116

50

58

N*

-

12m + 3m after OLZ

8w

8w

24m

Follow up -

-

7 studies (n = 577): Placebo-control (3 studies, n = 257); Discontinuation (2 studies, n = 33); Psychiatric, SGA-naı¨ve control (2 studies, n = 287)

SGA: 97.4 (RIS: 32.2; QTP: 5.9; OLZ: 19.3; ARI: 36.2; CLZ: 0.8; ZIP: 3.0); FGA: 2.6 (19 studies, n = 2123)

Control group

RIS: 0.62 mg/d

MOL: 59.9 mg/d (10 -- 140 mg/d); OLZ : 11.4 mg/d (2.5 -- 20 mg/d); RIS: 2.8 mg/d (0.5 -- 6 mg/d) OLZ: 5.1 mg ± 2.1 (1.25 -- 10)

RIS: 4.0 mg/d ± 1.2; OLZ: 12.3 mg/d ±3.5; HAL: 5.0 mg/d ± 2.0

RIS: 0.89 mg/d ± 0.51; OLZ: 8.88 mg/d ± 3.36, QTP: 183 mg/d ± 145

Mean dose*

RIS: 97.3, OLZ: 2.7, QTP: 5.4

OLZ: 100

MOL: 34.5; OLZ : 30.2; RIS: 35.3

SCZ: 66; SzAD: 34

AN: 68.02, ED NOS-A (with features of AN): 17.02; ED NOS: 14.89

RIS: 38; OLZ: 32; HAL: 30

RIS: 69; OLZ: 10; QTP: 21


PSY: 52; Mood d/o: 48

PSY: 31; MD: 14; tic d/o: 9; DBD: 34; Other d/o: 12

Diagnosis (%)*

ADHD inattentive: 21.6; ADHD combined: 73; ODD: 54.1; ANX: 16.2; Learning disability: 21.6; CD: 10.8; PDD 10.8; BPD: 10.8 MD: 30.6 (Mood Male: 59.2 (19 studies, n = 2123); NOS: 4.3; DEP: 2.9; BPD: 23.4); DBD/ Caucasian: 62.0 (16 studies, n = 1850) ADHD: 17.7; PSY (SCZ, SzAD, PSY): 31.8; ANX: 2.7; ED: 2.3; Substance abuse: 0.0005; PDD/autism: 19.2; Tic d/o: 1.7 (18 studies, n = 2074) Male: 86.5; Caucasian: 78.4; Asian: 3.7; Aboriginal: 7.4; Other: 3.7

Male: 4.25

Male: 65; Caucasian: 64; AA: 29; Hispanic: 4; Other: 7



Male (%)*; Race (%)*


Weiss et al. (2009) (Canada) [57]

Sikich et al. (2008) (USA) [55]


LS: Retrospective chart review of AP-naı¨ve patients participating in a “SGA monitoring program” (2003 -- 2007) LS: Double-blind, randomized, 8w study of RIS, OLZ and HAL in psychotic youths LS: Double-blind study on different APs in early onset SCZ/SzAD (TEOSS-Study 2002 -- 2006)

Design and setting

Roy et al. (2010) (Canada) [53]

Study/country

Table 1. Design, demographic and treatment characteristics of studies providing data on glucose metabolism dysfunction in antipsychotic-treated youths (continued).




Table 2. Glucose, HbA1c, insulin- and HOMA-IR-change associated with antipsychotics in youths. Outcome Glucose change

Study (year) Calarge et al. (2014) (USA) [42]

Outcome measurement FBS (mg/dl): BL and 1.5 years f/u


FBS $ 100 mg/dl: BL and 1.5 years f/u n (%)

Correll et al. (2009) (USA) [17]

FBS change (mg/dl): BL to 12w f/u

FBS $ 100 mg/dl: BL to 12w f/u, n/N (%)


FBS change (mg/dl): BL to 12w f/u BL to 26w f/u


FBS $ 125 mg/dl: BL to 26w f/u, n (%) FBS change (mg/dl): BL to 6w f/u


FBS $ 110 mg/dl: BL and 4w f/u, n (%)

Fraguas et al. (2007) (Spain) [46]

FBS (mg/dl): BL and change to 6 m f/u

Outcome

Association

RIS Cont: BL: 91.4 ± 9.9, 1.5 years Comparing groups: BL: p > 0.9, f/u: 89.6 ± 10.3; SGA Cont: BL: 91.3 ±4.0, 1.5 years 1.5 years f/u: p > 0.8 f/u: 91.4 ± 25.0; RIS Disc: BL: 91.6 ±85, 1.5 years f/u: 90.0 ± 5.0; RIS Cont: BL: 7 (10%), 1.5 years f/u: 7 (11%); SGA Cont: BL: 0 (0%), 1.5 years f/u: 2 (22%); RIS Disc: BL: 4 (25%), 1.5 years f/u: 0 (0%)

Comparing groups: BL: p > 0.2, 1.5 years f/u: p > 0.1

ARI: 0.54 (95% CI: -2.85 -- 3.93); OLZ: 3.14 (95% CI: 0.69 -- 5.59); QTP: 2.64 (95% CI: -0.65 -- 5.93); RIS: 1.14 (95% CI: -0.84 -- 3.12); Control: 0.69 (95% CI: -4.84 -- 6.22);

p = 0.76; p = 0.02; p = 0.12; p = 0.26; p = 0.81

ARI: 2/41 (4.9%); OLZ: 1/45 (2.2%); QTP: 2/36 (5.6%); RIS: 4/135 (3.0%); Control: 0/15 (0.0%) ZIP 80 mg/d: 0.1 ±20.9, ZIP 160 mg/d: 3.7 ±11.9; ZIP all: -1.0 ± 13.1;

n.s.

ZIP all: 0 (0%) ARI (10 mg/d): 2.10 ± 12.65; ARI (30 mg/d): -0.98 ± 10.57; Placebo: -3.15 ± 14.43

n.s.

ARI (10 mg/d): BL: 2 (2.4%), 4w f/u: 1 (1.5%); ARI (30 mg/d): BL: 3 (3.5%), 4w f/u: 2 (3.1%); Placebo: BL: 1 (1.3%), 4w f/u: 1 (1.9%)

n.s.

All: BL: 79.2 ± 7.9, 6 m f/u: +1.6 ± 10.3;

Change scores RIS versus OLZ, RIS versus

* “normal” < 100 mg/dl; “impaired/IGT” ‡ 100 mg/dl and < 126 mg/dl; “high” ‡ 126 mg/dl. z “Risk factors for diabetes mellitus”: family history of diabetes in a first-degree relative, being overweight or at risk of being overweight (BMI > 85th percentile for age and sex), high-risk ethnicity (Native American, African-American, Latino, Asian-American, Pacific Islander), being habitually physically inactive, having delivered a baby weighing > 9 lbs or having been diagnosed with gestational diabetes mellitus, HDL < 35 mg/dl or a triglyceride level > 250 mg/dl, hypertension (> 95th percentile for age, sex, height), impaired FBS or impaired glucose tolerance, other conditions associated with insulin resistance (acanthosis nigricans, polycystic ovary syndrome) or a history of vascular disease. ARI: Aripiprazole; BL: Baseline; BMI: Body mass index; CLZ: Clozapine; Cont: Continuation; d: Days; Disc: Discontinuation; FBS: Fasting blood sugar; FI: Fasting insulin; f/u: Follow up; GT: Glucose tolerance; HAL: Haloperidol; HbA1c: Hemoglobin A1c; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model assessment for insulin resistance; IGT: Impaired glucose tolerance; m: Months; N/A: Not available; n.s.: Not significant; OLZ: Olanzapine; QTP: Quetiapine; RIS: Risperidone; MOL: Molindone; SGA: Second-generation antipsychotic; T2DM: Type 2 diabetes mellitus; w: Weeks; ZIP: Ziprasidone. Expert Opin. Drug Saf. (2014) 14(2)

7


Table 2. Glucose, HbA1c, insulin- and HOMA-IR-change associated with antipsychotics in youths (continued).


Outcome

Study (year)

Outcome measurement

Haas et al. (2009) (USA) [47]

FBS change (mg/dl): BL and change to 3w f/u

Khan et al. (2009) (USA) [48]

FBS (mg/dl): BL FBS $ 100 mg/dl: BL and end point, n (FBS)


FBS change (mg/dl): BL to end point: Change of groups* (n, mean change %)

Kumra et al. (2008) (USA) [35]

FBS change (mg/dl): BL and change to 12w f/u

FBS $ 100 mg/dl: BL and 12w f/u, n (%, FBS)

Marcus et al. (2011) (USA) [49]

FBS (mg/dl): BL and median percentage change

FBS $ 115 mg/dl: n/N (%)

Outcome

Association

RIS: BL: 77.8 ± 8.9, 6 m f/u: +0.6 ± 10.8; OLZ: BL: 82.2 ± 6.3, 6 m f/u: +3.1 ± 10.4; QTP: BL: 78.1 ± 8.0, 6 m f/u: +1.2 ± 10.3

QTP, OLZ versus QTP: n.s.

RIS (0.5 -- 2.5 mg/d): BL: 86.5 ±10.8, 3w f/u: +3.6 ±16.2; RIS (3 -- 6 mg/d): BL: 84.7 ±10.8, 3w f/u: +5.4 ± 9.0; Placebo: BL: 90.1 ±9.0, 3w f/u: -1.8 ± 9.0

n.s.

OLZ: BL: 83.8 ±14.4; RIS: BL: 89.3 ±13.8;

OLZ versus RIS: p = 0.179

OLZ: BL: 1, end point:1 (102 mg/dl); RIS: BL: 4; end point: 4 (110.3 mg/dl) OLZ: +3.13 IGT to high GT: n = 13, 23.1% (95% CI: 5 -- 53.8%); normal to high GT: n = 108, 0.9% (95% CI: 0 -- 5%); nnormal/IGT to high GT: n = 121, 3.3% (95% CI: 0.9 -- 8.2%) CLZ: BL: 89.6 ±16.4, 12w f/u: 94.1 ±16.8; OLZ: BL: 80.4 ±9.1; 12w f/u: 84.0 ±7.7 ; CLZ: BL: 0/18 (0%), 12w f/u: 1/17 (5.8%); OLZ: BL: 0 (0%), 12w f/u: 0/21 (0.0 %) ARI: BL: 88 mg/dl; £ 3 m: 1.6%; 3 -- 6 m: 0.0%; 6 -- 9 m: 0.0%; > 9 m: 2.1%; ARI: £ 3 m: 3/189 (1.6%); 3 -- 6 m: 1/106 (0.9%); 6 -- 9 m: 2/141 (1.4%); > 9 m: 3/154 (1.9%)

Compared to adults: n.s. n.s.

p = 0.86

n.s.

N/A

N/A

* “normal” < 100 mg/dl; “impaired/IGT” ‡ 100 mg/dl and < 126 mg/dl; “high” ‡ 126 mg/dl. z “Risk factors for diabetes mellitus”: family history of diabetes in a first-degree relative, being overweight or at risk of being overweight (BMI > 85th percentile for age and sex), high-risk ethnicity (Native American, African-American, Latino, Asian-American, Pacific Islander), being habitually physically inactive, having delivered a baby weighing > 9 lbs or having been diagnosed with gestational diabetes mellitus, HDL < 35 mg/dl or a triglyceride level > 250 mg/dl, hypertension (> 95th percentile for age, sex, height), impaired FBS or impaired glucose tolerance, other conditions associated with insulin resistance (acanthosis nigricans, polycystic ovary syndrome) or a history of vascular disease. ARI: Aripiprazole; BL: Baseline; BMI: Body mass index; CLZ: Clozapine; Cont: Continuation; d: Days; Disc: Discontinuation; FBS: Fasting blood sugar; FI: Fasting insulin; f/u: Follow up; GT: Glucose tolerance; HAL: Haloperidol; HbA1c: Hemoglobin A1c; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model assessment for insulin resistance; IGT: Impaired glucose tolerance; m: Months; N/A: Not available; n.s.: Not significant; OLZ: Olanzapine; QTP: Quetiapine; RIS: Risperidone; MOL: Molindone; SGA: Second-generation antipsychotic; T2DM: Type 2 diabetes mellitus; w: Weeks; ZIP: Ziprasidone.

8





Outcome

Study (year)

Outcome measurement

Margari et al. (2013) (Italy) [50]

FBS (mg/dl): BL, Ø-6 m f/u and change (%)

Ngai et al. (2014) (Canada) [51]

FBS (mg/dl):

Panagiotopoulos et al. (2009) (Canada) [52]

FBS $ 100 mg/dl: n/N (%) FBS $ 126 mg/dl: n/N (%)

Roy et al. (2010) (Canada) [53]



Swenne et al. 2011 (Sweden) [56]

HbA1c change

Weiss et al. (2009) (Canada) [57] Fraguas et al. (2007) (Spain) [46]

Outcome RIS: BL: 84.1 ±7.4, Ø-6 m f/u: 87.1 ±9.7; change: 3.5%, SGA-naı¨ve: 79.3 (95% CI: 73.9 -- 82.9); RIS: 81.1 (95% CI: 77.5 -- 86.5); QTP: 79.3 (95% CI: 77.5 -- 86.5)

Association p = 0.25

Differences between QTP, RIS and SGA-naı¨ve: p = 0.568

SGA-naı¨ve: 6/80 (7.5%); SGA: 9/65 (13.8%); SGA-naı¨ve: 0/80; SGA: 5/65 (7.7%)

FBS (mg/dl): BL, change to 3 m f/u (%) and RIS/OLZ/QTP: BL: 87.1 ± 7.3; to 6 m f/u (%) 3-month f/u: -1.1% ±12.5, 6 m f/u: +1.8% ± 10.3 FBS (mg/dl): BL and 8w f/u RIS: BL: 86.9 ±17.8; 8-w f/u: 79.0 ±19.8; OLZ: BL: 87.2 ±10.8; 8-w f/u: 97.2 ± 14.4; HAL: BL: 87.8 ± 13.0; 8-w f/u: 87.5 ± 12.9 FBS (mg/dl): BL, change to 8w f/u MOL: BL: 84.0 ±10.6; 8w f/u: +0.9 (95% CI: -4.3 -- 6.1); OLZ: BL: 86.9 ± 12.0; 8w f/u: +0.6 (95% CI: -9.4 -- 10.6); RIS: BL: 83.8 ± 8.0; f/u: +1.2 (95% CI: -2.0 -- 4.4) FBS (mg/dl): BL (before OLZ), 4w f/u, 3m OLZ: BL: 79.3 ± 7.6; f/u, 6m f/u, 12m f/u, 3m after 4w f/u: 81.1 ± 8.1; 3 m f/u: 82.0 ± OLZ f/u 8.3; 6 m f/u: 82.0 ± 7.0; 12 m f/u: 86.5 ± 8.7; 3 m -after OLZ f/u: 84.7 ±5.4 FBS $ 100 mg/dl: n/N (%) SGA: 5/24 (20.8%) HbA1c (%): BL and change to 6 m f/u: All: BL: 4.0 ± 1.7, 6 m f/u: +0.5 ±1.2; RIS: BL: 4.3 ± 1.7, 6 m f/u: +0.3 ±0.8; OLZ: BL: 4.1 ± 1.1, 6 m f/u: + 0.2 ±0.8; QTP: BL: 3.6 ± 2.1, 6 m f/u: + 0.9 ± 1.6.

p = 0.01

p = 0.6 (3 m) p = 0.4 (6 m)

p = 0.457 p = 0.0645 p = 0.844

n.s.

p = 0.025

N/A Change score RIS versus OLZ, RIS versus QTP, OLZ versus QTP: n.s.



9


Table 2. Glucose, HbA1c, insulin- and HOMA-IR-change associated with antipsychotics in youths (continued). Outcome


Insulin change

Study (year)

Outcome measurement


HbA1c (%): BL (before OLZ), 4w f/u, 3 m f/u, 6 m f/u, 12 m f/u, 3 m after OLZ f/u

Calarge et al. (2014) (USA) [42]

FI (mU/ml): BL and 1.5 years f/u

FI $ 22 mU/ml: BL and 1.5 years f/u, n (%)


Ngai et al. (2014) (Canada) [51]

FI-Change (mU/ml): BL to 12w f/u

FI (mU/ml):

Proinsulin (pmol/L):

Proinsulin:insulin ratio:

Matsuda index (insulin sensitivity): Insulinogenic Index (insulin secretion): Insulin secretion-sensitivity index-2 (ISSI-2, a-cell function):

Outcome

Association

OLZ: 4.4 ±0.4; 4w f/u: 4.3 ± 0.3; 3 m f/u: 4.2 ± 0.4; 6 m f/u: 4.1 ± 0.3; 12 m f/u: 4.3 ± 0.4; 3 m after OLZ f/u: 4.4 ±0.3

n.s.

RIS Cont: BL: 6.9 ± 5.0, 1.5 years f/u: 7.2 ± 6.9; SGA Cont: BL: 8.2 ± 6.5, 1.5 years f/u: 10.0 ± 3.6; RIS Disc: BL: 6.3 ± 3.1, 1.5 years f/u: 7.6 ± 6.1;

Comparing groups: BL: p > 0.6, 1.5 years f/u: p < 0.06;

RIS Cont: BL: 1 (2%), 1.5 years f/u: 3 (5%); SGA Cont: BL: 1 (13%), 1.5 years f/u: 0 (0%); RIS Disc: BL: 0 (0%), 1.5 years f/u: 1 (6%). The change in age-sex-specific BMI score between the two research visits was significantly correlated with the age-sex-adjusted change total insulin ARI: 2.61 (95% CI: -2.00 to 7.31); OLZ: 2.71 (95% CI: 0.42 -- 5.00); QTP: 1.08 (95% CI:-2.80--4.96); RIS: 0.69 (95% CI: -0.86--2.24); Control: -0.47 (95% CI: -4.31 -- 3.37) SGA-naı¨ve: 7.7 (95% CI:6.7 -- 9.7); RIS: 8.6 (95% CI:7.8 -- 10.1); QTP: 7.6 (95% CI:7.0 -- 10.6); SGA-naı¨ve: 15.2 (95% CI:11.5 -- 20.4); RIS: 16.3 (95% CI:12.6 -- 22.1); QTP: 15.0 (95% CI:11.8 -- 22.5); SGA-naı¨ve: 2.0 (95% CI:1.2 -- 2.5); RIS: 1.9 (95% CI:1.4 --2.6); QTP: 2.0 (95% CI:1.3 -- 2.5) --

Comparing groups: BL: p > 0.2, 1.5 years f/u: p = 1

p < 0.03

p = 0.28 p = 0.02 p = 0.59 p = 0.39 p = 0.81 p = 0.512 (differences between groups);

p = 0.681 (differences between groups);

p = 0.947 (differences between groups);

n.s. QTP < SGA-naı¨ve QTP < SGA-naı¨ve

p = 0.007; p = 0.008


10





Outcome

HOMA-IR change

Study (year)

Outcome measurement


FI (mU/ml): BL and change to 8w f/u


FI (mU/ml): BL (before OLZ), 4w f/u, 3m f/u, 6 m f/u, 12 m f/u, 3 m after OLZ f/u FI $ 12.95 mU/ml: n/N (%) HOMA-IR: BL and 1.5 years f/u

Weiss et al. (2009)z (Canada) [57] Calarge et al. (2014) (USA) [42]

HOMA-IR $ 4.39: BL and 1.5 years f/u, n (%)

“Risk factors for T2DM”


HOMA-IR: BL to 12w f/u


HOMA-IR: BL and change to 8w f/u

Khan et al. (2009) (USA) [48]

Increase of risk factors of T2DMz

Outcome MOL: BL: 10.0 ±7.9, 8w f/u: +1.2 (95% CI:-2.0 -- 4.3); OLZ: BL: 16.2 ±18.0, 8w f/u +15.7 (95% CI:-2.1 -- 33.5); RIS: BL: 14.6±17.2, 8w f/u: +2.4 (95% CI:-9.8 -- 5.0) Before OLZ: 4.1 ± 1.9; 4w f/u: 5.3 ± 2.6; 3 m f/u: 7.2 ± 4.5; 6 m f/u: 6.7 ± 3.2; 12 m f/u: 7.4 ± 1.7; 3 m after OLZ f/u: 7.3 ± 3.3 3/24 (12.5%)

Association OLZ-change compared to other groups: p = 0.034

p < 0.001

N/A

Comparing RIS Cont: BL: 1.58 ± 1.20, groups: BL: p > 0.6, 1.5 years f/u: 1.57 ± 1.59; 1.5 years f/u: p < 0.06 SGA Cont: BL: 1.86 ± 1.54, 1.5 years f/u: 2.40 ± 1.52; RIS Disc: BL: 1.46 ± 0.75, 1.5 years f/u: 1.68 ± 1.39; RIS Cont: BL: 2 (6%), 1.5 years f/u: 2 (5%); SGA Cont: BL: 0 (0%), 1.5 years f/u: 1 (25%); RIS Disc: BL: 0 (0%), 1.5 years f/u: 1 (9%). The change in age-sex-specific BMI score between the two research visits was correlated with the agesex-adjusted change of HOMA-IR

Comparing groups: BL: p = 1, 1.5 years f/u: p > 0.2

ARI: 0.55 (95% CI: -0.49 -- 1.59); OLZ: 0.62 (95% CI: 0.07 -- 1.17); QTP: 0.35 (95% CI:-0.57 -- 1.27); RIS: 0.20 (95% CI: -0.15 -- 0.55); Control: -0.09 (95% CI: -0.85 -- 0.67)

p = 0.31; p = 0.03; p = 0.46; p = 0.28; p = 0.82

MOL: BL: 2.4 ± 1.9; 8w f/u: +0.5 (95% CI: -0.4 -- 1.5); OLZ: BL: 2.1 ± 0.8; 8w f/ u: +1.2 (95% CI: -0.2 -- 2.6); RIS: BL: 2.3 ± 2.2; BL: 8w f/u: +0.0 (95% CI: -0.9 -- 0.8)

n.s.

OLZ-group; RIS-group

p = 0.008; p = 0.782

p < 0.07



11

12

< 0.0001 -

p value versus p value versus p value versus p value versus HbA1c (%)


0.55 (N/A) (N = 1, n = 41)

-

p value versus control p value versus olanzapine Fasting HOMA-IR

p value versus control P value versus olanzapine p value versus risperidone

HbA1c: Hemoglobin A1c.

2.61 (N/A) (N = 1, n = 41)

p value versus control p value versus olanzapine Fasting insulin (mU/ml)

control aripiprazole olanzapine risperidone

1.50 (-0.58, 3.6) (N = 3, n = 573)

Aripiprazole

Fasting glucose (mg/dl)

Outcome (± 95% CI)

< 0.0001 -

< 0.0001 0.91 (-2.77, 4.59) (N = 2, n = 80)

9.2 (-73.32, 91.73) (N = 2, n = 80)

< 0.0001 < 0.0001 0.05 (-1.85 -- 1.96) (N = 2, n = 67)

4.04 (1.47, 6.61) (N = 8, n = 369)

Olanzapine 0.40 (-2.9, 3.7) (N = 8, n = 490) < 0.0001 < 0.0001 < 0.0001 0.3 (N/A) (N = 1, n = 22) 1.13 (-1.64, 3.9) (N = 3, n = 277) 0.0007 < 0.0001 0.06 (-0.23, 0.36) (N = 3, n = 277) 0.935 < 0.0001 -

Risperidone 1.8 (-0.06, 3.66) (N = 3, n = 72) < 0.0001 0.0032 < 0.0001 0.0027 0.9 (N/A) (N = 1, n = 24) 1.08 (N/A) (N = 1, n = 36) 0.35 (N/A) (N = 1, n = 36) -

Quetiapine

-

-

-

-

3.7 (N/A) (N = 1, n = 63)

Ziprasidone

-

-

-

4.5 (N/A) (N = 1, n = 18) -

Clozapine

-

-

-

-0.3 (N/A) (N = 1, n = 15) -

Haloperidol

1.2 (N/A) (N = 1, n = 40) 0.5 (N/A) (N = 1, n = 40) -

0.9 (N/A) (N = 1, n = 40) -

Molindone

Control

-

0.07 (-1.9 -- 2.03) (N = 2, n = 33)

0.42 (-10.82, 11.66) (N = 2, n = 33)

-

-1.47 (-3.99, 1.01) (N = 4, n = 191)

Table 3. Change in fasting glucose, hbA1c, insulin and insulin resistance with antipsychotics versus controls and within antipsychotics groups.




secretion) and the insulin secretion-sensitivity index-2 (ISSI-2, b-cell function) (n = 36) [51]. Patient and treatment characteristics The mean patient age was 13.3 years (studies = 4, n = 442). About 57.4% of them were male (studies = 6, n = 594) and 56.1% were white (studies = 5, n = 547). Compared to the studies reporting on FBS change, more patients with ADHD and DBD were included in the studies reporting on insulin/insulin resistance change (psychosis: 33.7%, ADHD and DBD: 31.3%, mood disorders: 23.0%, mood disorder NOS: 5.7%, depression: 10.1%, bipolar disorder: 7.2%, PDD/autism: 7.9%, anxiety: 6.1%) (6 studies, n = 594). Most patients were treated with risperidone (56.1%), followed by olanzapine (21.6%), quetiapine (9.1%), aripiprazole (6.9%) and molindone (6.7%).


3.2.2

Control groups, type of matching Only two of the studies reporting on both insulin and HOMA-IR-included control groups, which consisted of patients who did not continue taking an antipsychotic at the beginning of the study (n = 33) [17,42]. The study focusing on proinsulin, Matsuda index, insulinogenic index and the ISSI-2 compared the results to a SGA-naı¨ve control group that was matched for age, sex, ethnicity, BMI standardized for age and sex, pubertal status, degree of psychiatric illness, psychiatric diagnoses and other medications [51]. 3.2.3

Change in fasting insulin and HOMA-IR Both olanzapine (9.2 µU/ml, 95% CI: -6.56 to 5.58, p < 0.0001) and risperidone (1.13 µU/ml, 95% CI: -1.64 to 3.9, p = 0.007) were associated with significantly greater insulin increases compared to controls (0.42 µU/ml, 95% CI: -10.82 to 11.66). The insulin change with olanzapine was also significantly higher than with risperidone (p < 0.0001) (Table 3). Insulin increases were 2.61 µU/ml with aripiprazole, 1.20 µU/ml with molindone and 1.08 µU/ml with quetiapine (one study each). HOMA-IR also increased the most with olanzapine (0.91, 95% CI: -2.77 to 4.59) and differed significantly from controls (0.07, 95% CI: -1.9 to 2.03), as well as from risperidone (0.06, 95% CI: -0.23 to 0.36, p < 0.0001), whereas risperidone was not significantly different from controls (p = 0.935). HOMA-IR increases were 0.55 with aripiprazole, 0.35 with quetiapine and 0.5 with molindone (one study each). 3.2.4

Studies reporting on the prevalence or incidence of T2DM 3.3.1 Study characteristics 3.3

Most of the studies reporting on DM in youths treated with antipsychotics were longitudinal (studies = 8, n = 57,867); only two studies (n = 7619) were cross-sectional (Table 4) [26,31,32,43,52,58-63]. The mean duration of the longitudinal studies was 1.57 years. The most common definitions of T2DM were T2DM diagnosis and/or antidiabetic medication

(both: 5 studies, 50.0%). Four studies (40.0%) used FBS ‡ 125/126 mg/day to define T2DM. Plasma glucose ‡ 200 mg/dl, HbA1c ‡ 7% and a questionnaire were used in only one study each (10%). Four studies compared data with a healthy control group (n = 246,828), five studies had a psychiatric control group (n = 61,784) and two studies did not have a control group (Table 4). Patient and treatment characteristics The mean age at study inclusion was 14.2 years (range 0 -- 24) and 57.4% of patients were male. Diagnoses were mentioned in nine studies (n = 58,030). Most patients had either mood disorders (50.8%) (consisting of mood disorder NOS: 28.0%; depression: 9.5%; or BPD: 9.3%) or DBD (46.4%). Severe mental illness was described in 33.6% of the antipsychotic-treated cohorts (psychosis: 8.2%, BPD: 9.1%, psychosis or BPD: 16.5%). Less common were substance abuse (6.0%), anxiety (3.5%), PDD/autism (1.1%) and tic disorder (0.0002%) (Table 4). All studies provided data regarding antipsychotic class treatment, showing that the majority of subjects received SGAs (86.3%, n = 56,509), 10.4% received FGAs (n = 6837) and 3.3% received FGA + SGA co-treatment (n = 2140). Details about specific antipsychotics were reported in eight studies (n = 46,500), indicating the largest use of risperidone (48.1%), followed by olanzapine (19.5%) and quetiapine (16.1%) (Table 4). 3.3.2

Control groups, type of matching In the four studies that included healthy controls, subjects were either matched to those exposed to antipsychotics on age, gender and calendar year of initial dispensing of the antipsychotic (using propensity score matching in a secondary analysis) [31] or matched on age only [63], without any matching procedures in the remaining two studies [58,59]. In the five studies including a psychiatric control group, subjects were either matched to those exposed to antipsychotics on age, gender, calendar year of initial dispensing of the antipsychotic drug, mental health and developmental conditions, oral corticosteroids, frequency of ambulatory care visits and use of other psychotropic medications (primary analysis: regression analysis; secondary analysis: propensity scores) [31] or matched on age, race, gender, intensity of enrollment, duration of prior psychiatric drug use, psychiatric diagnoses in past year, psychiatric medication in past year, conditions associated with metabolic disorders and cardiovascular conditions and adjusted by propensity score (using 115 covariates that included demographic characteristics, psychiatric diagnoses and medications, metabolic disorders and related conditions, obstetric-gynecologic conditions, cardiovascular disease, respiratory disorders, musculoskeletal symptoms, other somatic conditions and intensity of healthcare utilization [medical surveillance] for both psychiatric and somatic comorbidities) [32]. In the three remaining studies, psychiatric controls were not matched [52,58,60]. 3.3.3


13

14


9350

63

Male: 67

Male: 50.5

13.6 (10-17)

15.2 (13 -- 17)

Male: 56

Male: 60

Male (%)*; race (%)* SGA: 100

Antipsychotic treatment (%)*

SCZ/BPD: 100

BPD: 73; SCZ/ SzAD: 27

SGA: 94.9; FGA: 1.1; combination: 4.0

ZIP: 100

MD: 70,9 RIS: 37; QTP: 20; (BPD: 18.3; OLZ: 20 DEP: 19.3; Mood NOS: 33.3); ADHD:38.9; CD: 25.3, ANX: 20.6; alcohol abuse:3.1; other substance abuse: 8.9

Autism: 5.8; DBD: 55.2; MD: 68.5; SCZ: 4.9

Diagnosis (%)*

Healthy controls: General population without SCZ/BPD and without antipsychotic use (n = 188,784); psychiatric controls: Patients with SCZ or BPD and without antipsychotic use (n = 8740)

-

Healthy controls: No psychotropic medication use (n = 38,544); psychiatric controls: Antidepressant use (n = 26,265) Psychiatric controls: Recent initiators of other psychotropic drugs (n = 14,429)

Control group (N)

* Of the SGA-medicated subgroup. ADHD: Attention-deficit-hyperactivity disorder; ARI: Aripiprazole; BPD: Bipolar disorder; CD: Conduct disorder; CLZ: Clozapine; d: Days; CSS: Cross-sectional study; DBD: Disruptive behavior disorder; DEP: Depression; d/ o: Disorder; HAL: Haloperidol; LS: Longitudinal study; m: months; MD: Mood disorder; N/A: Not available; NOS: No otherwise specified; OLZ: Olanzapine; PDD: Pervasive developmental disorder; PSY: Psychosis; QTP: Quetiapine; RIS: Risperidone; SCZ: Schizophrenia; SGA: Second-generation antipsychotic; SzAD: Schizoaffective disorder; T2DM: Type 2 diabetes mellitus; ZIP: Ziprasidone.

Enger et al. (2013) (USA) [58]


28, 858 14.5 (6 -- 24)

LS: Data from 1.32 years Tennessee Medicaid program augmented with linkage to a statewide hospital discharge database and computerized birth certificates (1996 -- 2007) LS: Open-label study 0.51 years of the tolerability of oral ZIP consisting of a 3-week fixed-dose period and a subsequent 24-week flexible-dose period LS: Retrospective 1.31 years cohort study from Ingenix National Health Informatics database (1997 -- 2006)

N/A (5 -- 18)

Age, years* (range)

Bobo et al. (2013) (USA) [32]

N*

9636

Mean duration

LS: Retrospective study 0.38 years using administrative databases of three health maintenance organizations (2001 -- 2008)

Design and setting

Andrade et al. (2011) (USA) [31]

Study/country

Table 4. Design, demographic and treatment characteristics of studies reporting on T2DM in antipsychotic-treated youths.




SCZ: 47.7; bipolar mania: 45.3; prodromal to PSY: 7

OLZ: 100

DBD/ADHD: 43; RIS: 93; QTP: 8; PDD: 34; Cognitive OLZ: 2; CLZ: 0.002 impairment/ developmental d/ o: 17; ANX: 6; MD: 5; PSY: 5; Tic d/o: 5 N/A CLZ: 5.6; OLZ: 14.1; RIS: 26.8; phenothiazines: 33.8; HAL: 8.4; thioxanthines: 8.4; sulpiride: 2.8

RIS: 39,5; QTP: 6,4; OLZ: 7,9; ARI: 0,9; ZIP: 2,1; HAL: 0.8; combination (‡ 1 SGA or SGA + FGA): 42.3


-

Enrollees in the same age group not treated with antipsychotics

Healthy controls: Random sample without psychotropic medication use (n = 4500); psychiatric controls: Patients treated with antimanic (n = 3657) or antidepressant medications (n = 12,081) -

Control group (N)


5370

Male: 69.2; White:73.3, African: 11; Hispanic: 8.6; Asian: 0.6; Other: 3.5

15.8 (13 -- 17)

179

0.49 years

N/A

N/A (0 -- 24)

Male: 78

7456


Diagnosis (%)*

Male: 68.2; SCZ: 8.6; major Caucasian: 41; affective d/o: 54.6; African-American: 40.6; other psychotic d/ Hispanic: 0.3 o: 27.8; CD/ ODD: 71.7; ADHD: 78.7

Male (%)*; race (%)*

CSS: Retrospective analysis of a large health maintenance organization drug claim database comparing the prevalence of diabetes in different age groups (1998 -- 2004) LS: Database of six 0.55 years studies focusing on long-term-exposure of OLZ in youths

10 (2 -- 15)

10.4 ± 3.6

Age, years* (range)

Hammerman et al. (2008) (Israel) [62]

4140

N*

420

5.59 years

Mean duration

LS: Prospective, 2.37 years observational cohort study of SGA-initiating youths (April -- July 2003)

LS: Retrospective cohort study evaluation medical and pharmacy Medicaid claims (1996 -- 2005)

Design and setting

HarrisonWoolrych et al. (2007) (New Zealand) [61]

McIntyre et Jerrell (2008) [59]/Jerrell (2010) (USA) [60]

Study/country

Table 4. Design, demographic and treatment characteristics of studies reporting on T2DM in antipsychotic-treated youths (continued).



15

16

LS: Retrospective, new-user cohort study using Medicaid claims data (July 2004 -- June 2006)

Design and setting


163

N*

Ø 1.57 years 65,486 (8 studies, n = 57,867)

-

Mean duration

14.2 (7 studies; n = 43,024)

13.7 ± 2.71

N/A (6 -- 17)

Age, years* (range)

Male: 57.4 (9 studies, n = 58,030); White: 55.5 (3 studies, n = 9689)

Male: 62

Male: 63.9; White: 66.1; Black: 12.3; Other: 21.3; unknown: 0.4

Male (%)*; race (%)*

MD: 50.8 (Mood NOS: 28.0; DEP: 9.5; BPD: 9.3, other: 4.0); DBD/ADHD: 46.4; PSY (SCZ, SzAD, PSY NOS): 8.2; Severe mental illness (PSY and BPD): 33.6; (PSYCH: 8.0 BPD: 9.1, one of both: 16.5); ANX: 3.5; Substance abuse: 6.0; PDD/ autism: 7.9; Tic d/o: 0.0002 (9 studies, n = 58,030)

PSY: 17; MD: 25; ANX: 12; DBD: 23; PDD: 9; substance abuse: 3

All/6 -- 12 years/ 13 -- 17 years: Severe mental illness (SCZ/ SzAD/PSY): 48.1/38.9/ 58.6

Diagnosis (%)*

SGA: 86.3, FGA: 10.4; combination: 3.3 (10 studies, N = 65,486) Details on SGA: RIS: 48.1; QTP: 16.1; OLZ: 19.5; ARI: 0.1; CLZ: 0.5; ZIP: 0.4; SGA without details: 15.3 (8 studies; N = 46,500)

RIS: 35.3; QTP: 41.2; OLZ: 14.7; CLZ: 2.9; > 1 SGA: 5.9

SGA: 100; RIS: 50.5


Healthy controls: N =246,828 (4studies) Psychiatric controls: N = 61,784 (5 studies)

Psychiatric controls: SGA-naı¨ve patients with psychiatric disorders (n = 269)

Healthy controls: Children on albuterol and without antipsychotic use (n = 15,000)

Control group (N)


Panagiotopoulos et al. CSS: Retrospective chart review of all (2009) (Canada) [64] child and adolescent psychiatry emergency admissions (2005 -- 2007) 8 LS (n = 57,867); 2 CSS (n = 7619);

Morrato et al. (2010) (USA) [63]

Study/country

Table 4. Design, demographic and treatment characteristics of studies reporting on T2DM in antipsychotic-treated youths (continued).




Prevalence of T2DM in youths treated with antipsychotics, healthy and psychiatric controls

3.3.4


The T2DM prevalence was about 1.5 times higher (OR = 1.450, 95% CI = 1.101 -- 1.911, p = 0.006) in antipsychotic-medicated youths (11.5 T2DM cases/1000 patients, studies = 2, n = 21,109, raw prevalence = 242) than in psychiatric controls (7.9 T2DM cases/1000 patients, studies = 2, n = 8820, raw prevalence = 70), and about eight times higher (OR = 8.176, 95% CI = 7.139 -- 9.362, p < 0.0001) than in healthy controls (1.4 T2DM cases/1000 persons, n = 1,584,341, raw prevalence = 2244) (Table 5). Incidence of T2DM in youths treated with antipsychotics, healthy and psychiatric controls

3.3.5

The T2DM incidence was significantly lower (OR = 0.783, 95% CI = 0.683 to 0.897, p < 0.0001) in antipsychoticmedicated youths (6.2 T2DM cases/1000 patients, 8 studies, n = 57,867, incident cases = 356) than in psychiatric controls (incidence = 8.0 T2DM cases/1000 patients, 4 studies, n = 65,172, incident cases = 524), but about 3.5 times higher (OR = 3.475, 95% CI = 3.019 to 4.001, p < 0.0001) than in healthy controls (1.8 T2DM cases/1000, 4 studies, n = 246,828, incident cases = 450) (Table 5). However, one study contributing 24.1% of the psychiatric control patients contributed 89.3% of the T2DM cases in the pooled psychiatric control group, having an incidence of 29.7/1000 patients [60]. After removing this outlying study, which lacked any matching of the control group, in which 25% could apparently have even been co-prescribed antipsychotics, the T2DM incidence was over five times higher (OR = 5.376, 95% CI = 4.004 to 7.233, p < 0.0001) in antipsychotic-medicated youths (6.1 T2DM cases/1000 patients, 7 studies, n = 48,517,incident cases = 294) than in psychiatric controls (incidence = 1.1 T2DM cases/1000 patients, 3 studies, n = 49,434, incident cases = 56) (Table 5). 4.

Moderators of T2DM risk

Patient characteristics Younger patient age was associated with greater risk of T2DM in antipsychotic-treated patients relative to the risk in similarly aged control groups in two studies. First, one study that compared the prevalence of T2DM across different age groups reported a stronger association between T2DM and antipsychotic use in the younger age groups (0 -- 24 years: OR = 8.9) than in older age groups (25 -- 44 years: OR = 4.2; 45 -- 54 years: OR = 1.9; 55 -- 64 years: OR = 1.3; ‡ 65 years: OR = 0.93) [62]. Second, the dose-related risk of T2DM incidence observed in another study ([32], see below) was even more pronounced in youths aged 6 -- 17 years (p < 0.03). Conversely, two other studies reported a lower risk for children < 13 years of age compared to adolescents in the group of patients treated with antipsychotics [59,63]. 4.1

Antipsychotic treatment characteristics The T2DM prevalence risk was lower with SGAs compared to FGAs (OR = 0.7). Similarly, compared to the T2DM incidence with SGAs, Enger et al. [58] found higher T2DM incidences with FGAs (FGA: IR = 153.41/10,000 personyears; SGA: IR = 52.79/10,000 person-years, hazard ratio [HR] = 3.39) and with combined antipsychotic treatment (IR = 128.33/10,000 person-years, HR = 1.68). Consistent with this latter finding, youths exposed to multiple antipsychotics were at a significantly higher risk of T2DM compared to those receiving monotherapy (OR = 2.36) [59]. Regarding specific antipsychotics, one study found significantly increased HRs for T2DM compared to psychiatric controls with all examined SGAs (risperidone = 2.20, olanzapine = 2.17, quetiapine = 2.76, aripiprazole = 7.72, ziprasidone = 4.15) [32]. Looking to differential risks with specific antipsychotics, one study found a significantly longer time from antipsychotic initiation to T2DM diagnosis in the aripiprazole group compared to other antipsychotics (HR = 35.92) [59]. Another study found that the risk of T2DM was increased with cumulative dose of all antipsychotics, which was especially true in risperidone (risperidone < 5 mg: HR = 1.76, risperidone 5 -- 99.9 mg: HR = 3.43, risperidone > 100 mg: HR = 5.61, p < 0.04) [32]. The same study found an increased risk of T2DM even within the first year of antipsychotic drug exposure (HR = 2.49), suggesting also that the risk remains elevated at least for the 1 year after antipsychotic discontinuation (HR = 2.57). 4.2

5.

Conclusion

The reviewed data indicate that FBS changes occurred early and were greater with all analyzable antipsychotic agents compared to control subjects, being highest with olanzapine, followed by quetiapine, which in turn was followed by aripiprazole, and being lowest with risperidone. Results for insulin increase and HOMA-IR were consistent, inasmuch as data were available. Moreover, T2DM prevalence was increased eightfold in antipsychotic users compared to healthy controls and was increased 1.5-fold compared to psychiatric controls. Further, T2DM incidence was 3.5-fold higher in antipsychotic users compared to healthy controls and fivefold higher compared to psychiatric controls after removal of one outlying study regarding both results and methodology. Among patient factors, younger age was significantly associated with a relatively greater risk of T2DM in antipsychotic users compared to controls. Among treatment factors, FGA use and combined antipsychotic use were associated with greater T2DM risk relative to control groups than SGA use, and T2DM risk increased with greater cumulative antipsychotic dose and follow-up time. 6.

Expert opinion

The association of antipsychotics with early adverse changes in glucose metabolism and the heightened risk of T2DM


17


Table 5. T2DM in antipsychotic-treated youths.


Study/country

T2DM definition

Prevalent cases (n/N)

Anrade et al. (2011) (USA) [31]

Diagnosis (ICD 9-CM 250.00-250.9X) and/or antidiabetic medication (excluding female ‡ 12 years receiving metformin only) and/or HbA1c ‡ 7%, fasting plasma glucose level ‡ 126 mg/dl or casual plasma glucose ‡ 200 mg/ dl

N/A

Bobo et al. (2013) (USA) [32]

Diagnosis and case definition or diagnosis and prescription for antidiabetic medication within 120d FBS ‡ 125 mg/d

N/A

DelBello et al. (2008) (USA) [43] Enger et al. (2013) (USA) [58]

McIntyre et Jerrell (2008) (USA) [59]/Jerrell (2010)

(USA) [60]

Diagnosis of diabetes (ICD-9 250. x, 790.2x, or V58.67) or antidiabetic medication

Diagnosis (ICD-9-CM 250 and 250.00-251.92 with the fifth digit 0 or 2)

Incident cases (n/N) Diabetes definition A or B: SGA: 12/9636 [ARI: 2/9636; CLZ: 0/9636; OLZ: 1/9636; QTP: 2/9636; RIS: 7/9636; ZIP: 0/9636]; NU: 26/38,544; AD: 19/26,265. Diabetes definition A, B or C: SGA: 15/9636 [ARI: 2/9636; CLZ: 0/9636; OLZ: 2/9636; QTP: 3/9636; RIS: 8/9636; ZIP: 0/9636]; NU: 38/38544; AD: 51/26265 SGA: 92/28,858 Psych-control: 14/14,429

N/A

ZIP: 0/63

AP use in SCZ/BPD: 80/9350; FGA in SCZ/BPD: 0/9350; SGA in SCZ/BPD: 73/9350; Combination in SCZ/BPD: 7/9350; NU: 557/18,878; Psych-Control: 70/8740 AP: 86/4140; NU: N/A

AP use in SCZ/BPD: 71/9350; FGA in SCZ/BPD: 2/9350; SGA in SCZ/BPD: 61/9350; Combination in SCZ/BPD: 8/9350; NU: 265/188,784; Psych-Control: 22/8740 AP: 125/4140; NU: 85/4500 AM+AD: 468/15,738

Harrison-Woolrych et al. (2007) (New Zealand) [61]

Questionnaire

N/A

SGA: 2/271

Hammerman et al. (2008) (Israel) [62]

Antidiabetic medication (insulin or oral hypoglycemic drugs)

N/A


FBS ‡ 126 mg/d

AP: 71/7456; SGA: 35/4504; FGA: 36/2952 [CLZ: 4/180; OLZ: 10/1100; RIS: 19/2812; phenothiazines: 24/2178; thioxanthines: 6/307; HAL: 6/467; sulpiride: 2/412]; NU: 1687/1,565,463 N/A

Morrato et al. (2010) (USA) [63]

Diagnosis (ICD 9-CM) or B: antidiabetic medication (oral or insulin) in the 180d after index date

N/A

SGA: All: 48/5370; 6 -- 12 years: 20/2850; 13 -- 17 years: 28/2520; NU: All: 74/15,000; 6 -- 12 years: 33/9000; 13 -- 17 years: 41/6000

Panagiotopoulos et al. (2009) (Canada) [64]

FBS ‡ 126 mg/d

SGA: 5/65; Psych-control: 0/80 AP: 242/21,109 (4 studies); NU: 2244/ 1,584,341 (2 studies); Psych-control: 70/8820 (2 studies)

N/A

T2DM-Diagnosis: 5 (50%) Antidiabetic medication: 5 (50%) FBS ‡ 125/126 mg/d: 4 (40%) Plasma glucose ‡ 200 mg/ dl: 1 (10%) Questionnaire: 1 (10%) HbA1c ‡ 7%: 1 (10%)

OLZ: 6/179

AP: 356/57,867 (8 studies); NU: 450/246,828 (4 studies); Psych-control: 524/65,172 (4 studies)

AD: Antidepressant; AM: Anti-manic; ANX: Anxiety disorder; AP: Antipsychotics, ARI: Aripiprazole; BPD: Bipolar disorder; CLZ: Clozapine; d: Days; FBS: Fasting blood sugar; FGA: First-generation antipsychotic; HAL: Haloperidol; HbA1c: Hemoglobin A1c; ICD: International classification of diseases; m: Months; N/A: Not available; NU: Non-users of psychotropic medication; OLZ: Olanzapine; QTP: Quetiapine; RIS: Risperidone; SCZ: Schizophrenia; SGA: Second-generation antipsychotic; T2DM: Type 2 diabetes mellitus; w: Weeks; ZIP: Ziprasidone.

18




associated with this class of medications have been well documented for adults [14]. This review summarized the available studies on antipsychotic effects on glucose metabolism in youths, showing that -- although hyperglycemia and T2DM seem fortunately to be rare in antipsychotic-treated youths -- the risk is significantly higher than in healthy controls in this age group. Most of the studies also reported an elevated risk of metabolic changes in antipsychotic-treated youths compared to psychiatric controls, yet this population was shown to generally be at intermediate in risk between antipsychotictreated and healthy control youths. The increased risk of glucose metabolism abnormalities in psychiatric controls not receiving antipsychotics is likely due to the association between mental illness, obesity, unhealthy lifestyle, lower socioeconomic class/poverty, adverse effects of non-antipsychotic psychotropic medications and possibly shared genetic effects that can each adversely affect glucose homeostasis [29]. Unfortunately, studies reporting on glucose changes and especially reporting on the distal/long-term adverse outcome of T2DM were scarce in youths, precluding detailed comparisons among and across many different antipsychotics. Particularly, data with FGAs were insufficient for statistical comparisons. Nevertheless, this review confirms that olanzapine affects glucose homeostasis the most among SGAs with sufficient data, underscoring recommendations to use olanzapine not as a first-line agent in first episode patients and in youths [14,17]. In adults, the risk of T2DM is higher with most SGAs compared to FGAs [14,16] and varies according to specific drugs [8,11]. The fact that two studies reported lower T2DM risk with SGAs than FGAs [58,62] may be due to the fact that, at least in youth, generally only very severely ill youths, who failed multiple SGA trials are prescribed FGAs. Thus, there may be a selection bias, in that more severely ill patients have or accumulated medication-unrelated risk factors of T2DM. The same reason may underlie the finding in two studies [58,59] that antipsychotic co-treatment was associated with greater T2DM risk. Although two of the included studies reported a greater relative risk for controls in younger age groups [32,62], two studies reported a lower risk for children < 13 years of age compared to adolescents [59,63]. This seeming disconnect is likely due to the different frame of reference. Since age is one of the most powerful risk factors of T2DM [64] and since BMI, another highly important risk factor of T2DM [65,66], tends to increase during adulthood [66], the individual risk contribution of antipsychotics will be most detectable in younger individuals in whom less of the nonspecific risk factors have accumulated. Accordingly, higher relative risk or ORs are found in youths treated with antipsychotics compared to control groups than in adults [19,61], even though actual incidence rates are obviously lower in younger individuals. The results from this study need to be interpreted within its limitations. In particular, this review is limited by the low number of studies with relevant data as well as the

heterogeneity of the design, ascertainment strategies, sample characteristics, assessments and matching procedures to the respective control groups. For example, statistical comparisons regarding change in glucose, HbA1c, insulin and HOMA-IR were restricted to only few antipsychotics with data from ‡ 2 studies. Further, the summarized data must be evaluated cautiously, as studies were mostly not randomized or not prospective in nature, and head-to-head comparisons were lacking. Therefore, biases could have affected the results, including selective testing of individuals and reporting of outcomes, as well as confounding by indication, in that patients at higher risk for metabolic abnormalities and T2DM are often treated with lower risk antipsychotics and vice versa. Further, since T2DM is a long-term adverse effect, the risk is likely insufficiently captured in the reviewed studies that lasted on average little more than 1.5 years. However, this exact reason, the need for long-term observation, makes sufficiently large randomized or, at least, prospective studies less feasible, necessitating register and database studies, which require careful adjustment of risk factors that may differ systematically across the compared populations. Nevertheless, despite these limitations, this is the first systematic review that comprehensively evaluates the pooled prevalence and incidence of glucose metabolism changes and T2DM in youths treated with antipsychotics, comparing the results with psychiatric and healthy control subjects. In summary, the results from this systematic review indicate that antipsychotics are associated with an increased risk of worsening of glucose homeostasis that starts early and that can develop into T2DM. This risk, as well as relative differences among individual antipsychotics, should be considered when making the decision to start or continue antipsychotic treatment and when selecting among individual agents [13,15,17,67]. Moreover, inadequately low monitoring of cardiovascular risk factors and changes during antipsychotic treatment in youths [63] needs to be remedied, giving way to routine and proactive monitoring and management of cardiovascular risk in youth with mental illness and especially those in need of antipsychotic treatment [13,27,68-71]. Patients and parents should be informed about the potential cardiometabolic adverse effects of antipsychotics and should be supported in counteracting these changes by healthy nutrition and physical activities. Further research is needed in order to more precisely characterize the timing and extent of dysregulation of glucose metabolism with specific antipsychotics and in different patient subgroups. Such studies need to be sufficiently large, include representative samples, control for relevant covariates when using control groups, be sufficiently long and use comprehensive and standardized assessments of glucose metabolism aberrations to allow for comparison and data pooling across studies. In order to ameliorate cardiometabolic risk and burden associated with antipsychotics, research into the exact molecular mechanisms of this adverse effect cluster is needed, so that interventions can be directed at these molecular targets or that medications can be developed that are devoid of such


19


adverse effects. Finally, non-pharmacological prevention and intervention methods need to be developed, tested and implemented that are scalable, affordable and that patients and families can adhere to. The fact that currently not a single randomized controlled behavioral weight loss intervention study in youths treated with or started on antipsychotics exists [72] needs to be remedied to inform clinicians about the most effective strategies to reduce or counteract antipsychoticinduced weight gain and metabolic abnormalities.


Declaration of interest The work was partially supported by the National Institute of Mental Health Advanced Center for Services and Intervention Research, the Zucker Hillside Hospital (P30MH090590). Bibliography

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Affiliation

Britta Galling1 & Christoph U Correll†1,2,3 † Author for correspondence 1 Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11001, USA 2 Hofstra North Shore LIJ School of Medicine, Hempstead, NY, USA 3 Feinstein Institute for Medical Research, Manhasset, NY, USA E-mail: [email protected]


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Type 2 diabetes in children and adolescents on atypical antipsychotics.

Diabetes risk potentially underestimated in youth and children receiving antipsychotics.

Risk of diabetes in children and adolescents exposed to antipsychotics: a nationwide 12-year case-control study.

Do SSRI Antidepressants Increase The Risk of Extrapyramidal Side Effects In Patients Taking Antipsychotics?

Do Interventions to Increase Walking Work? A Systematic Review of Interventions in Children and Adolescents.

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Antidepressants increase risk of behavioural symptoms in children and adolescents with depression or anxiety.

Antipsychotics in children and adolescents with schizophrenia: a systematic review and meta-analysis.

The effect of antidepressants and antipsychotics on weight gain in children and adolescents.

Antipsychotics use in children and adolescents: An on-going challenge in clinical practice.

Atypical antipsychotic initiation and the risk of type II diabetes in children and adolescents.

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Atypical antipsychotics for psychosis in adolescents.

Possible mechanisms for the skeletal effects of antipsychotics in children and adolescents.

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Longitudinal Correlates of Health Risk Behaviors in Children and Adolescents with Type 2 Diabetes.

Atypical antipsychotics for psychosis in adolescents.

SENTIA: a systematic online monitoring registry for children and adolescents treated with antipsychotics.

Do uterotonic drugs increase risk of abruptio placentae and eclampsia?

Type 2 diabetes in Sudanese children and adolescents.

Serum proinsulin in children and adolescents with chemical diabetes.

Fear of hypoglycemia in children and adolescents with diabetes.

Type 2 diabetes mellitus in children and adolescents.

Complications of Diabetes Diagnosed in Children and Adolescents-Reply.