Comparison of Long-Term (At Least 24 Weeks) Weight Gain and Metabolic Changes Between Adolescents and Adults Treated with Olanzapine

Abstract

Objective:

The purpose of these analyses was to compare the weight and other metabolic changes between adolescents and adults during long-term (at least 24 weeks) olanzapine treatment.

Method:

The adult database included 86 studies with 12,425 patients with schizophrenia, schizoaffective disorder, depression, borderline personality disorder, or bipolar I disorder; the adolescent database comprised six studies with 489 patients with schizophrenia, schizoaffective disorder, borderline personality disorder, bipolar I disorder, or prodromal psychosis. Patients who had at least 24 weeks of olanzapine exposure (N=4,280 from adult database and N=179 from adolescent database) were analyzed in this study. Weight data were collected for all patients, fasting glucose and lipids data were collected in some patients. For weight gain, data in 34.5% adults (4,280/12,425) and 36.6% adolescents (179/489) were analyzed while for glucose and lipids, data in 8.4% (1,038/12,425) adults and 24.9% adolescents (122/489) were analyzed. Adult patients were treated with oral (5–20 mg/day) or depot formulations (doses equivalent to oral doses of 5–20 mg/day) of olanzapine and adolescent patients were treated with oral olanzapine (2.5–20 mg/day). The incidences of potentially clinically significant categorical changes in weight and metabolic parameters were calculated with a 95% confidence interval (CI). Nonoverlapping 95% CIs were considered as indicating a statistically significant difference. Weight, lipid, and glucose change comparisons are summarized.

Results:

The mean age for adolescents and adults was 15.8 and 38.8, respectively. The percentage of the male population was similar for both adults (58.5%) and adolescents (62.8%). The median duration of the follow-up period was 201 days for adolescent database and 280 days for adult database. The mean weight gain from baseline to endpoint in adolescents was 11.24 kg when compared with 4.81 kg in adults. The 95% CI for adolescents (10.1, 12.4) and adults (4.57, 5.04) are not overlapping, which indicates that the difference between adolescents and adults is statistically significant. The percentage of olanzapine-treated adolescents with ≥7% mean weight gain was 89.4% compared with 55.4% in adults (Number need to harm [NNH]=3). Mean changes from baseline to endpoint were also greater for adolescents than for adults in fasting total cholesterol (5.49 mg/dL vs. 2.06 mg/dL), LDL (5.41 mg/dL vs. 0.49 mg/dL), and triglycerides (20.49 mg/dL vs. 16.72 mg/dL), but overlapping 95% CIs were observed for all lipid parameters. Mean changes from baseline to endpoint in fasting glucose values were similar between adolescents and adults (3.13 mg/dL vs. 3.95 mg/dL). However, the incidence of treatment-emergent significant glucose changes was greater in adults. Among olanzapine-treated adults and adolescents, 8.9% and 0.9% experienced a shift from normal to high and 12.5% and 3.3% experienced a shift from normal/impaired glucose tolerance (IGT) to high fasting glucose, respectively. The incidence of IGT to high elevations in glucose was greater in adolescents, but overlapping 95% CI was observed.

Conclusions:

The types of metabolic changes during the long-term olanzapine treatment in adolescents were similar to those observed in adults. However, the magnitude of changes in weight and lipid parameters was greater in adolescents. Patients should receive regular monitoring of weight, fasting blood glucose, and lipid profile at the beginning of, and periodically during, treatment with olanzapine.

Introduction

A pproximately 10% of adults suffer from mental disorders worldwide, whereas in adolescents, the prevalence ranges from 0.4% to 17% (World Health Organization 2004; Carlson et al. 2005). Schizophrenia usually begins during adolescence, and 39% of the patients experience their first episode before the age of 20 (Häfner 1995). Similarly, 20% of patients in whom bipolar I disorder is diagnosed manifest their first manic episode during adolescence, with the peak age ranging between 15 and 19 years (Goodwin and Jamison 1990). When compared with adults, adolescents with either schizophrenia or bipolar I disorder demonstrate poorer outcomes and greater functional and psychosocial impairment (Werry et al. 1991; Lewinsohn et al. 1993; McClellan et al. 1993; Strober et al. 1995; Wozniak et al. 1995; Carlson et al. 2000).

Olanzapine is an atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder in adults (Beasley et al. 1996; Tollefson et al. 1997; Tran et al. 1998; Tohen et al. 1999, 2003, 2004; Glick et al. 2001). A few typical antipsychotics are approved for the treatment of schizophrenia and bipolar I disorder in adolescents (Moban [package insert] 2008; Mellaril [package insert] 2009; Navene [package insert] 2009; Thorazine [package insert] 2009) and currently, four atypical antipsychotics—aripiprazole, risperidone, quetiapine, and olanzapine—have been approved for use in adolescents (DelBello et al. 2007; Tohen et al. 2007; Correll 2008; Findling et al. 2008, 2009; Haas et al. 2009; Kryzhanovskaya et al. 2009a, 2009b; Seroquel [package insert] 2009; Zyprexa [package insert] 2009). Quetiapine has recently received approval for the treatment of schizophrenia and bipolar mania in 13–17-year-old and 10–17-year-old patients, respectively (Seroquel [package insert] 2009). FDA approved olanzapine for treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adolescents aged 13–17 years old on December 4, 2009 (Zyprexa [package insert] 2009). Olanzapine is not approved for the treatment of borderline personality disorder. Although the efficacy of olanzapine in the treatment of adolescents with schizophrenia and bipolar I disorder has been demonstrated (Tohen et al. 2007; Kryzhanovskaya et al. 2009a), changes in weight and other metabolic parameters were observed in short-term clinical trials (Correll et al. 2009; Kryzhanovskaya et al. 2009a, 2009b). A recent comparison between placebo-controlled, short-term clinical trials of olanzapine-treated adolescents and adults in whom schizophrenia or bipolar I disorder were diagnosed showed that weight gain, hepatic transaminases, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and prolactin levels, and the incidence rate of sedation were greater in adolescents than in adults (Kryzhanovskaya et al. 2009a, 2009b; Zyprexa [package insert] 2009). The increased potential for weight gain and hyperlipidemia in adolescents compared with adults and the potential long-term risks may lead clinicians to consider prescribing other drugs first for adolescents. To extend these findings, we further explored differences in metabolic changes (weight, lipids, and glucose) between the two populations during long-term olanzapine treatment. A larger sample of clinical trial patients with a variety of diagnoses (schizophrenia, schizoaffective and schizophreniform disorders, bipolar I disorder, borderline personality disorder, or prodromal to psychosis) was included in these analyses.

Method

Databases of olanzapine-treated adolescents and adults

Weight and metabolic parameters including glucose and lipid levels from the integrated adolescent olanzapine treatment database (“adolescent database,” Table 1a, Kryzhanovskaya et al. 2009a, 2009b) were compared with the integrated adult olanzapine treatment database (“adult database”). The adolescent database included 489 patients from six oral olanzapine studies sponsored by Eli Lilly and Company [HGIN (Kryzhanovskaya et al. 2009a), HGIU (Tohen et al. 2007), LOAY (Dittmann et al. 2008), HGMF (Lobo et al. 2010), HGKL (Schulz et al. 2008), and HGGF (McGlashan et al. 2006)]. The adolescent database included four adolescent studies: HGIN, HGIU, LOAY, and HGMF. In addition, 4 borderline personality disorder adolescent patients from the study HGKL and 24 prodromal to psychosis adolescent patients from the study HGGF were included in the database. Schizophrenia, schizoaffective disorder, borderline personality disorder, bipolar I disorder (manic or mixed episodes), or prodromal to psychosis (Table 1b) were diagnosed in these patients. The majority of patients were Caucasian males with a mean age of 15.8 years. The dose range was 2.5–20.0 mg/day, with a mean modal dose of 11.30 mg/day.

Table 1a.

Summary Overview of Adolescent Olanzapine Treatment Databases

Study (reference)	Length (weeks)	Age, mean (range) (Years)	Number of Patients (enrolled or randomized)	Diagnosis	Number of patients with at least 24 weeks olanzapine exposure
HGIN (Kryzhanovskaya et al. 2009a)	6 Double-blind 26 Open-label	16.1 (13–18)	107	Schizophrenia	59
HGIU (Tohen et al. 2007)	3 Double-blind 26 Open-label	15.1 (13–17)	161	Bipolar I Disorder (manic or mixed episodes)	80
LOAY^a (Dittmann et al. 2008)	24 Open-label	12–17	96	Schizophrenia Schizoaffective Schizophreniform disorders	26
HGMF (Lobo et al. 2010)	4.5 Open-label	13–17	107	Schizophrenia Bipolar I Disorder (manic or mixed episodes)	0
HGKL (Schulz et al. 2008)	12 Double-blind 12 Open-label	15–17	4	Borderline Personality Disorder	0
HGGF (McGlashan et al. 2006)	52 Double- blind	13–17	24	Prodromal to Psychosis	14

Study enrolled patients from 12 to 21 years of age, but only patients from 13 to 17 years were included in this database.

Table 1b.

Summary of Integrated Adult and Adolescent Olanzapine Treatment Databases

	Databases
	Adult	Adolescents
No. of studies	86	4 adolescent studies plus 28 patients in 2 adult studies
Total no. of patients in the database (Overall)	12,425	489
Total no. of patients with at least 24 weeks exposure (Analyzed)	4,280 (34.5% of 12,425)	179 (36.6% of 489)
Gender (Overall)	Female: 41.5%; Male: 58.5%	Female: 37.2%; Male: 62.8%
Gender (Analyzed)	Female: 38.7%; Male: 61.3%	Female: 30.8%; Male: 69.2%
Race (Overall)	African: 14.4%	African: 10.8%
	Western Asian: 0.7%	Caucasian: 77.5%
	Caucasian: 67.6%	East/Southeast Asian: 0.4%
	East/Southeast Asian: 7.6%	Hispanic: 8.6%
	Hispanic: 7.9%	Other: 2.7%
	Other: 1.7%
Race (Analyzed)	African: 10.8%	African: 11%
	Western Asian: 0.8%	Caucasian: 73.3%
	Caucasian: 69.1%	East/Southeast Asian: 0.6%
	East/Southeast Asian: 6.9%	Hispanic: 11.6%
	Hispanic: 10.2%	Other: 3.5%
	Other: 2.2%
Distribution of diagnoses (Overall)	Schizophrenia or related disorders : 73.2%	Schizophrenia or schizoaffective disorder: 47.2%
	Bipolar I disorder:	Bipolar mania: 32.1%
	Bipolar mania: 12%	Bipolar I disorder (manic or mixed episodes): 14.3%
	Bipolar depression: 5.1%	Prodromal to psychosis: 5.5%
	Borderline personality disorder: 5.1%	Borderline personality disorder: 0.8%
	Treatment-resistant depression: 3.3%
	Psychotic depression: 0.8%
	Agitation schizophrenia: 0.4%
	Prodromal schizophrenia: 0.1%
Distribution of diagnoses (Analyzed)	Schizophrenia or related disorders: 85.8%	Schizophrenia: 47.7%
	Bipolar I disorder:	Bipolar mania: 45.3%
	Bipolar mania: 10.2%	Prodromal to psychosis: 7%
	Bipolar depression: 1.4%
	Borderline personality disorder: 2.4%
	Prodromal schizophrenia: 0.1%
Dose forms (Overall)	Oral or depot	Oral
Dose forms (Analyzed)	Oral or depot	Oral
Mean modal dose (Overall)	13.3 mg	11.3 mg
Mean modal dose (Analyzed)	14.1 mg	12.1
Mean age (Overall)	38.8	15.8
Mean age (Analyzed)	38.4	15.7
Mean BMI (Overall)	27.2	23.7
Mean BMI (Analyzed)	26.5	23.1

BMI=body mass index; No.=number.

The adult database included 12,425 patients from Lilly sponsored 86 studies of oral and depot formulations of olanzapine. The patients were diagnosed as having schizophrenia (or related disorders such as schizophreniform or schizoaffective disorder), bipolar I disorder, borderline personality disorder, or depression (Table 1a). The majority of adult patients were also Caucasian males with a mean age of 38.8 years. The dose range was 5.0–20.0 mg/day, with a mean modal dose of 13.30 mg/day. The included studies provided data of patients with long-term exposure to olanzapine for at least 24 weeks. We selected the 24-week time point, because data from the three key adolescent studies (HGIN, HGIU, and LOAY) were collected at 24 weeks. Patients who had at least 24 weeks of olanzapine exposure (N=4,280 from adult database and N=179 from adolescent database) were analyzed in this study. Weight data were collected for all patients, fasting glucose and lipids data were collected in some patients. For weight gain, data in 34.5% adults (4,280/12,425) and 36.6% adolescents (179/489) were analyzed. For glucose and lipids, data in 8.4% (1,038/12,425) adults and 24.9% adolescents (122/489) were analyzed. This time frame also provided us a meaningful sample size for the analyses and comparisons. Among the patients who were in olanzapine studies with at least 24 weeks duration, 45.5% of adolescents and 48.2% of adults actually completed 24 weeks of olanzapine treatment. Studies HGIN and HGIU assessed the efficacy and safety of olanzapine in the treatment of adolescent aged 13 to 17 years with schizophrenia and acute manic or mixed episodes associated with bipolar disorder, respectively (Tohen et al. 2007; Kryzhanovskaya et al. 2009a). Study LOAY enrolled patients from 12 to 21 years of age, but only patients from 13 to 17 years were included in the assessment of the efficacy of olanzapine in improving overall symptomatology in adolescents with schizophrenia, schizoaffective, and schizophreniform disorders (Dittmann et al. 2008). Study HGMF examined the pharmacokinetics of olanzapine in adolescents with schizophrenia or bipolar I disorder from 13 to 17 years (Lobo et al. 2010). Both HGKL (Schulz et al. 2008) and HGGF (McGlashan et al. 2006) were adult studies that included 4 adolescent patients with borderline personality disorder (HGKL) and 24 adolescent patients with prodromal to psychosis (HGGF). All study procedures were conducted in accordance with the ethical standards of the responsible committees on human experimentation (institutional or regional) or with the Declaration of Helsinki 1975, revised Hong Kong 1989.

Measurement and analyses of metabolic parameters

All analyses presented in this study were conducted on all adolescent and adult patients who had at least 24 weeks of exposure. The median duration of the follow-up period is 202 days for adolescent database and 325 days for adult database. Mean changes on weight and metabolic parameters were summarized, and the 95% confidence intervals (CI) for each relevant measure were calculated. Incidence of potentially clinically significant categorical changes in weight and metabolic parameters was calculated with 95% CI. For lipid analyses, adolescent categories are based on the National Cholesterol Education Program (NCEP) pediatric panel report, and adult categories are based on NCEP Adult Treatment Program (ATP) III guidelines (NCEP 2002). Glucose categories were defined according to American Diabetes Association (ADA) criteria (ADA 2009). Fasting (≥8 hours) glucose and lipid data were collected at baseline and at endpoint. Potentially clinically significant weight gain was defined as weight gain ≥7%, 15% and 25% of baseline weight. Patients who had glucose elevations (following ADA guidelines) or lipid elevations (as per NCEP recommendations) at least once during the course of treatment were included in the reported rates of treatment emergent categorical changes in fasting glucose and lipid values in patients treated with olanzapine, respectively.

Data analysis

There was no statistical comparison between long-term adult and adolescent integrated databases. Descriptive comparison and 95% CI analysis for each population was performed. Non-overlapping 95% CIs were considered as significantly different. All analyses presented were conducted on all patients who had at least 24 weeks of exposure. Estimates of exposure are provided both for total treatment exposure of the patients included in the analysis, and the exposure up to the time of the relevant measure (time until measurement used as endpoint in mean change analyses). In addition, 95% CIs of each measure in each population were compared between adolescents and adults.

Results

Weight changes

Adolescent patients treated with olanzapine for at least 24 weeks showed mean weight increase of 11.24 kg from baseline to endpoint, whereas olanzapine-treated adults showed mean weight increase of 4.81 kg (Table 2), indicating that adolescents had greater mean increases in weight when compared with adults. Since the 95% CIs for adolescents (10.1, 12.4) and adults (4.57, 5.04) are not overlapping, the difference of weight increases between adolescents and adults were considered statistically significant. Nonoverlapping 95% CIs indicate a statistically significant difference. In analyses of potentially clinically significant weight gain; 89.4%, 55.3%, and 29.1% of the adolescents experienced at least 7%, 15%, and 25% weight gain from baseline, respectively. Percentages of adult patients with at least 24 weeks of exposure meeting the 7%, 15%, and 25% weight gain from baseline were lower when compared with adolescents: 55.4%, 24.1%, and 8.0%, respectively (Table 2). The z-score and the percentiles for weight and body mass index were also increased significantly from baseline to endpoint (Kryzhanovskaya et al. 2009b). However, weight gain in olanzapine-treated adolescent patients was still significant even when the normal growth is factored in.

Table 2.

Mean Change from Baseline to Endpoint in Weight and Treatment-Emergent Clinically Significant Weight Gain in Patients Treated with Olanzapine for At Least 24 Weeks

Variable (N=number of patients)	Adult estimate (95% CI) (SD) (N=4,280)	Adolescent estimate (95% CI) (SD) (N=179)	95% CI overlap
Mean weight change (kg)	4.81 (4.57, 5.04) (7.91)	11.24 (10.1, 12.4) (7.7)	No
Median exposure (days)	280	201
Incidence of weight gain (%)/Median exposure (days)
≥7%	55.4% (53.9, 56.9) 83	89.4% (83.9, 93.5) 31	No
≥15%	24.1% (22.8, 25.4) 159	55.3% (47.7, 62.7) 104	No
≥25%	8.0% (7.2, 8.8) 250	29.1% (22.5, 36.3) 139	No

CI=confidence interval; SD=standard deviation.

Glucose changes

A greater percentage of adolescents compared with adults experienced a shift from borderline to high (23.10% vs 21.70%, number need to harm [NNH]=71), but there was an overlap in the 95% CI. There were similar mean changes from baseline to endpoint in fasting glucose in adolescents treated with olanzapine (3.13 mg/dL) when compared with adults (3.95 mg/dL), but the rate of categorical changes (i.e., shifts from normal to high and normal/impaired glucose tolerance [IGT] to high) was greater in adults than in adolescents. Among olanzapine-treated adults and adolescents with at least 24 weeks of exposure, 8.9% and 0.9% experienced a shift from normal to high (NNH=−12) and 12.5% and 3.3% experienced a shift from normal/IGT to high fasting glucose (NNH=−11), respectively (Table 3). Since the 95% CIs for adults and adolescents are not overlapping in these categories, the differences of glucose changes between adults and adolescents were also considered statistically significant.

Table 3.

Mean Change from Baseline to Endpoint in Fasting Glucose Values and Treatment-Emergent Categorical Changes in Fasting Glucose Values in Patients Treated with Olanzapine for At Least 24 Weeks

Variable (mg/dL)	Adult mean change (95% CI) (SD)	Adolescent mean change (95% CI) (SD)	95% CI overlap
	(N=1,038) 3.95 (2.47, 5.43) (24.35)	(N=121) 3.13 (0.7, 5.55) (13.47)	Yes
Incidence of elevations (%)
Normal to high (<100 to ≥126 mg/dL)	(N=716) 8.9% (7%, 11.3%)	(N=108) 0.9% (0%, 5.1%)	No
IGT to high (≥100 and <126 mg/dL to ≥126 mg/dL)	(N=276) 21.7% (17%, 27.1%)	(N=13) 23.1% (5%, 53.8%)	Yes
Normal/IGT to high (<126 mg/dL to ≥126 mg/dL)	(N=992) 12.5% (10.5%, 14.7%)	(N=121) 3.3% (0.9%, 8.2%)	No

IGT=impaired glucose tolerance; N=number.

Lipid changes

Mean changes from baseline to endpoint in fasting total cholesterol, LDL cholesterol, and triglyceride levels were greater for adolescents than adults. In long-term studies (at least 24 weeks), olanzapine-treated adolescents had mean increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.49, 5.41, and 20.49 mg/dL, respectively, compared with 2.06, 0.49, and 16.72 mg/dL in olanzapine-treated adults. There was also a greater mean decrease in high-density lipoprotein (HDL) cholesterol levels in adolescents (−4.52 mg/dL) when compared with adults (−1.17 mg/dL) (Table 4). Comparison of the 95% CIs indicated the greater decrease of HDL in adolescents (−5.97, −3.08), which is statistically significant compared with adults (−1.79, −0.55).

Table 4.

Mean Change from Baseline to Endpoint in Fasting Lipids in Patients Treated with Olanzapine for At Least 24 Weeks

Variable (mg/dL)	N1=Number of adult patients; N2=Number of adolescent patients	Adult mean change (95% CI; SD)	Adolescent mean change (95% CI; SD)	95% CI overlap
Total cholesterol (mg/dL)	N1=1,031; N2=122	2.06 (−0.11, 4.24; 35.55)	5.49 (1.24, 9.73; 23.69)	Yes
LDL cholesterol (mg/dL)	N1=1,011; N2=121	0.49 (−1.40, 2.38; 30.57)	5.41 (1.54, 9.27; 21.45)	Yes
HDL cholesterol (mg/dL)	N1=1,016; N2=122	−1.17 (−1.79, −0.55; 10.05)	−4.52 (−5.97, −3.08; 8.06)	No
Triglycerides (mg/dL)	N1=1,029; N2=122	16.72 (10.18, 23.26; 106.93)	20.49 (7.9, 33.09; 70.26)	Yes

HDL=high-density lipoprotein; LDL=low-density lipoprotein.

The incidence of treatment-emergent changes in fasting total cholesterol, LDL cholesterol, and triglyceride levels was also generally greater in olanzapine-treated adolescents than in olanzapine-treated adults. When compared with adults, olanzapine-treated adolescents had a greater incidence of change from borderline to high (57.6%, NNH=6% vs. 42.0% in adults) in total cholesterol; change from normal to high (10.9%, NNH=14% vs. 4.0% in adults) and borderline to high (47.6%, NNH=5% vs. 25.8% in adults) in LDL cholesterol, and change from normal to high triglycerides (36.4%, NNH=9% vs. 24.8% in adults) (Table 5), but overlapping 95% CIs were observed for all lipid parameters.

Table 5.

Treatment-Emergent Categorical Changes in Patients Treated with Olanzapine for At Least 24 Weeks

Variable	Adult definition according to 2002 NCEP ATP III Guidelines (mg/dL)	% (N)	Percentage 95% CI	Adolescent definition according to 1992 NCEP Pediatric Panel Report (mg/dL)	% (N)	Percentage 95% CI	95% CI overlap
Fasting total cholesterol
Normal to high	<200 to ≥240	10.2% (570)	(7.8, 13.0)	<170 to ≥200	7.7% (78)	(2.9, 16.0)	Yes
Borderline to high	≥200 and <240 to ≥240	42.0% (293)	(36.3, 47.9)	≥170 and <200 to ≥200	57.6% (33)	(39.2, 74.5)	Yes
Increase ≥40 mg/dL	Increase ≥40	25.9% (1,031)	(23.2, 28.7)	Increase ≥40	14.8% (122)	(9.0, 22.3)	No
Fasting LDL cholesterol
Normal to high	<100 to ≥160	4.0% (273)	(2.0, 7.1)	<110 to ≥130	10.9% (92)	(5.3, 19.1)	Yes
Borderline to high	≥100 and <160 to ≥160	25.8% (586)	(22.3, 29.5)	≥110 and <130 to ≥130	47.6% (21)	(25.7, 70.2)	Yes
Increase ≥30 mg/dL	Increase ≥30	32.0% (1,011)	(29.2, 35.0)	Increase ≥30	22.3% (121)	(15.2, 30.8)	Yes
Fasting HDL cholesterol
Normal to low	≥40 to <40	37.2% (629)	(33.4, 41.1)	>65 to <35	0.0% (11)	(0.0, 28.5)	No
Borderline to low	NA			≥35 and ≤65 to <35	21.0% (100)	(13.5, 30.3)	NA
Decrease ≥20 mg/dL	Decrease ≥20	7.6% (1,016)	(6.0, 9.4)	Decrease ≥20	5.7% (122)	(2.3, 11.5)	Yes
Fasting triglycerides
Normal to high	<150 to ≥200	24.8% (640)	(21.5, 28.4)	<90 to >130	36.4% (66)	(24.9, 49.1)	Yes
Borderline to high	≥150 and <200 to ≥200	65.6% (163)	(57.8, 72.9)	≥90 and ≤130 to >130	64.5% (31)	(45.4, 80.8)	Yes
Increase ≥50 mg/dL	Increase ≥50	54.2% (1,029)	(51.1, 57.3)	Increase ≥50	45.9% (122)	(36.8, 55.2)	Yes
<500 to ≥500 mg/dL	<500 to ≥500	5.0% (1,011)	(3.8, 6.6)	<500 to ≥500	0.0% (122)	(0.0, 3.0)	No
<1,000 to ≥1,000 mg/dL	<1,000 to ≥1,000	0.8% (1,028)	(0.3, 1.5)	<1,000 to ≥1,000	0.0% (122)	(0.0, 3.0)	Yes

NCEP ATP=National Cholesterol Education Program Adult Treatment Program; LDL=low density lipoprotein; HDL=high density lipoprotein; CI=confidence interval.

Discussion

Changes in weight and metabolic parameters in adult patients with schizophrenia treated with atypical antipsychotics, including olanzapine, have been well documented in the literature in patients (Allison et al. 1999; McEvoy et al. 2005; Meyer et al. 2008; Newcomer 2009). Several factors have been suggested to explain weight changes during treatment with atypical antipsychotics. These include dysregulation of hormones (ghrelin, leptin and adiponectin) related to control of food intake, energy metabolism, and body weight (Gentile 2009). In this study, the percentage of olanzapine-treated adolescents with ≥7% mean weight gain was also greater compared with adults (NNH=3).

There is a critical need for treatment of adolescents with schizophrenia and bipolar I disorder, considering the severity of these illnesses, poor outcomes, and few approved treatments in this population. Although olanzapine has demonstrated short-term acute efficacy in adolescents with schizophrenia and manic or mixed episodes associated with bipolar I disorder (Tohen et al. 2007; Kryzhanovskaya et al. 2009a), changes in weight and other metabolic parameters have been observed (Correll et al. 2009; Kryzhanovskaya et al. 2009a, 2009b). Additional study of the potential long-term benefits and risks of olanzapine treatment in adolescents is needed. Understanding the potential for metabolic changes during long-term olanzapine treatment is important because of the potential health risks and possible impact on overall treatment compliance of adult and adolescent patients. A recent long-term analysis of overall mortality of adults with schizophrenia found a lower incidence of mortality in patients treated with antipsychotic drugs compared with patients not treated with antipsychotics. This reduced mortality in the treated sample was due to lower suicide rates (Tiihonen et al. 2009).

Studies of atypical antipsychotic use in children and adolescents have suggested that the younger patient population may be more susceptible to some metabolic adverse events, including rapid increase of weight gain during the course of treatment (Correll and Carlson 2006; Correll et al. 2006a, 2006b; Hammerman et al. 2008). In this article, we focused on comparing long-term metabolic changes in adults and adolescents treated with olanzapine. Both adults and adolescents showed changes in weight gain and lipid parameters, but the magnitude of these changes was greater in adolescents than in adults. These findings are consistent with other studies showing metabolic changes in adults and adolescents during long-term treatment with olanzapine (Zipursky et al. 2005; Fraguas et al. 2008; Perez-Iglesias et al. 2008; Arango et al. 2009).

Long-term olanzapine-treated adult patients with first-episode psychosis have experienced clinically significant weight gain within 1 year (10.9 kg, standard deviation [SD]=7.2) (Perez-Iglesias et al. 2008) and 2 years of treatment (10.2 kg, SD=10.1) (Zipursky et al. 2005). In addition, adolescents in whom schizophrenia and first-episode psychosis were diagnosed showed significant weight gain (5.5 kg) and increase in total cholesterol levels after 6 months of treatment with olanzapine (Fraguas et al. 2008; Arango et al. 2009). Similarly, in a 45-week study, clinically significant weight gain was noted in children and adolescents during olanzapine treatment when compared with adults (Fleischhaker et al. 2008).

In shorter-term olanzapine clinical trials, metabolic changes have been observed in olanzapine-treated adolescents in whom schizophrenia and bipolar I disorder are diagnosed (Patel et al. 2004; Correll et al. 2009; Kryzhanovskaya et al. 2009a, 2009b), but weight and lipid changes were greater than in adults (Ratzoni et al. 2002; Sikich et al. 2004; Fleischhaker et al. 2007; Kryzhanovskaya et al. 2009a, 2009b). Recently, Correll et al. (2009) also found a significant increase in weight and lipid levels in adolescents treated with atypical antipsychotics (including olanzapine). In this study, we have not compared weight gain between olanzapine-treated and other atypical antipsychotic-treated adolescents. The mean weight change in ≥24 week-olanzapine-treated adolescents (11.24 kg) was similar to weight gain during treatment with olanzapine from another adolescent long-term study (6 months) (15.5 kg) and also greater compared with quetiapine (5.5 kg) (Arango et al. 2009), as well as with risperidone (4.9 kg) (Sikich et al. 2004) and molindone (0.3 kg) in an 8-week study (Sikich et al. 2008). Greater changes for prolactin, hepatic transaminase elevation, and higher incidence of sedation-related adverse events were also observed in short-term olanzapine-treated adolescents compared with adults (Kryzhanovskaya et al. 2009a, 2009b; Zyprexa [package insert] 2009). In an NIH funded short-term Treatment of Early-Onset Schizophrenia Spectrum Disorders study, olanzapine-treated adolescents experienced significantly greater mean weight gain (6.1 kg), lipid changes, and insulin levels compared with risperidone (3.6 kg) and molindone (0.3 kg) (Sikich et al. 2008). These data are consistent with our long-term findings of increased incidence of weight gain and dyslipidemia; there was no comparison with other antipsychotic agents in the analyses of long-term data.

Limitations from this study included pooling data from many different studies that spanned a period of 10 years, inter-study variability that included different study designs, doses, strict inclusion and exclusion criteria of patient selection, and patient care or monitoring for metabolic-related adverse events. Although these variations do not allow a direct statistical comparison between these two populations, the comparison of the 95% CIs suggests greater weight and lipid changes in adolescents than in adults treated with olanzapine.

Conclusion

Clinical Significance

Weight gain is a risk factor for elevations in lipids and glucose (Correll and Carlson 2006). Hyperlipidemia and hyperglycemia have been associated with an increased risk of cardiovascular disease, stroke, blindness, kidney disease, and mortality (Srinivasan et al. 2002; Freedman et al. 2004; Correll et al. 2009). Therefore, when deciding among the alternative treatments for schizophrenia and bipolar I disorder available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should also consider the potential long-term risks when prescribing olanzapine to adolescents. In many cases, this may lead them to prescribe other drugs before selecting olanzapine.

Footnotes

Disclosures

Drs. Kryzhanovskaya, Xu, Millen, Acharya, Jen, and Osuntokun are employees of Eli Lilly. Drs. Kryzhanovskaya, Acharya, and Osuntokun are shareholders of Eli Lilly.

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