Introduction: The objective of this article was to identify the rates of patients ≤5 years of age who received recommended monitoring before and after second-generation antipsychotic (SGA) initiation and had an SGA metabolic adverse effect (MAE).

Methods: This was a retrospective cohort analysis conducted at Kaiser Permanente Colorado, an integrated health care delivery system, between January 1, 2002, and June 30, 2011. Commercially insured patients ≤5 years of age newly initiated on an SGA were included. Patients were followed for up to 3 years. Metabolic monitoring included lipid profile, blood glucose, blood pressure, and weight measurements. Patient characteristics and outcomes were described using descriptive statistics.

Results: A total of 40 patients were included. Overall, 2 (5.0%) patients received all recommended baseline monitoring, and no (0.0%) patients received all recommended follow-up monitoring. Weight monitoring was completed most frequently with rates of completion of 57.5%, 95.0%, 85.0%, and 76.5% at baseline and years 1, 2, and 3, respectively. At least 1 MAE was identified in 14/40 (35.0%), 5/28 (17.9%), and 2/17 (11.8%) patients during years 1, 2, and 3, respectively. The most frequent MAE identified was weight gain. Among patients identified with at least 1 MAE, 4/14 (28.6%), 2/5 (40.0%), and 2/2 (100%) received a behavioral intervention during years 1, 2, and 3, respectively.

Discussion: Overall, baseline and follow-up metabolic monitoring were poor. Future studies should focus on examining barriers to monitoring in order to improve health care quality.

The use of second-generation antipsychotics (SGA) in children ≤5 years of age is increasing despite limited FDA-approved indications.1-3  State-specific research2,4  in Medicaid populations has identified that antipsychotic use in children significantly increased over a 5-year period with rates of use in children ≤5 years of age ranging from 1.6% to 2.6%. Given the minimal benefit of SGA use in children, there are growing concerns about the risk of SGA-associated metabolic adverse effects (MAEs) and other associated abnormalities in this population.2-9 

Studies10-13  suggest that very young children may be the most susceptible to MAEs and endocrine abnormalities. Although monitoring can lead to early recognition of preventable SGA-induced MAEs, recommended monitoring, based on the American Diabetes Association and American Psychiatric Association (ADA/APA) joint guidelines,6  in children is not performed routinely.3,14 

The effects of SGA use in children ≤5 years old, particularly within an integrated health care delivery system (IHCDS), are unclear. Because Medicaid beneficiaries experience poorer health outcomes compared with IHCDS patients, it is important to understand SGA use in non-Medicaid pediatric patient populations.15  Thus, the purpose of this study was to evaluate SGA use, including rates of metabolic monitoring, MAEs, and management practices, in a population of children ≤5 years old.

Study Design and Setting

This was a retrospective cohort study of children ≤5 years of age who were newly initiated on an SGA (ie, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, paliperidone, and aripiprazole). Patients were followed for up to 3 years after SGA initiation or until discontinuation of all SGAs or health plan membership termination, whichever came first. This study was conducted among members of Kaiser Permanente Colorado (KPCO), an IHCDS with more than 500 000 members receiving care at 25 ambulatory clinics at the time of the study. Patients were cared for through the integrated efforts of mental health providers, including child psychiatrists, nurses, clinical pharmacy specialists, and therapists.

Lipid and blood glucose laboratory results are processed at KPCO's laboratories. Kaiser Permanente Colorado utilizes an electronic medical record (EMR; Health Connect®, Epic Systems, Madison, WI) with which coded and free-text medical, pharmacy, laboratory, death, etc, information is recorded. Study information was obtained from queries of KPCO administrative databases and verified via manual EMR reviews. This study was reviewed and approved by the KPCO Institutional Review Board.

Study Population

Children were included if they had an SGA newly initiated between January 1, 2002, and June 30, 2011, and were ≤5 years of age at time of initiation. A SGA was considered newly initiated if there was no history of a SGA prescribed in the 180 days prior to the first dispensing (index date) during the study period. Included children had received ≥60-day supplies of the SGA during the 180-day period following the index date and maintained continuous KPCO membership during the 180 days prior to and after the index date.

Data Collection

The study cohort was identified through queries of KPCO's electronic administrative databases. Manual EMR reviews were conducted to identify behavioral interventions for MAEs and verify study outcomes as needed. Lipid and blood glucose values, blood pressure and weight measurements, patient mental health indication(s), and comorbidities (ie, hypertension, diabetes mellitus) were extracted from the EMR database. Prescription medication dispensing information in the 180 days prior to and after the index date were obtained from the electronic KPCO pharmacy database.

Study Outcomes

The primary study outcome was the percentage of patients who received all recommended metabolic monitoring, per the ADA/APA guidelines, at baseline and first-year follow-up after SGA initiation. The 1-year monitoring period allowed for the greatest capture of monitoring and is consistent with National Committee for Quality Assurance quality metrics for health plan performance.16  Metabolic monitoring was defined as lipid profile (low-density lipoproteins and triglycerides), blood glucose, blood pressure, and weight measurements. Baseline monitoring was defined as having received a measurement during the 84 days prior to and up to 14 days after the index date. Follow-up monitoring was defined as having received a measurement during the first, second, and third years after the index date. Monitoring was assessed in patients who had at least one SGA dispensing and continued as a KPCO member during each follow-up year. For patients with a baseline monitoring in the 14 days after the index date, follow-up commenced on the day after the baseline monitoring date.

Secondary outcomes included an assessment of MAEs and any subsequent behavioral interventions for such effects. Behavioral interventions included diet and/or exercise counseling or referral to weight management for evaluation. An MAE was defined as weight ≥90th percentile, blood pressure >120/80 mmHg, triglycerides ≥110 mg/dL, or fasting blood glucose >100 mg/dL.11,13,17  If a patient had more than 1 metabolic measurement in a study period, the measurement most proximal to but before the index date was used for the baseline value, and the measurement most distal to and after the index date but before the end of the study period was used for the follow-up value. Additional outcomes included SGA (eg, interchange to another SGA) and health services (eg, inpatient stays, emergency department visits) utilization. Further, subanalysis was performed to identify blood pressure >110/70 mmHg to account for potential hypertension in younger children.

Patient age was determined as of index date. Mental health indications were categorized as anxiety, autism, bipolar disorder, depression, mood disorder, hyperkinetic disorder, psychotic disorder, other, and unknown. Prescriber departments were categorized as mental health, other (eg, family practice, neurology, pediatrics), and hospital/non-KPCO provider. Race was categorized as white and other/unknown/unreported. Metabolic monitoring is reported as the percentage of patients who received specific monitoring by discrete study time periods. Behavioral interventions, MAEs, and health services utilization are reported as percentages.

Forty patients were included and followed for a mean of 2.8 ± 0.8 years (Table 1). Patients were predominantly male, and the majority (57.5%) were 5 years of age. The majority of patients received risperidone as their index SGA with a median starting dose of 0.5 mg/d. The most common mental health indications were major depression and autism. Approximately half of prescribers were from the KPCO Mental Health Department. Although few patients had comorbidities, 5 patients were diagnosed with developmental delay.

TABLE 1: 

Patient characteristics

Patient characteristics
Patient characteristics

Overall, 2 patients received all recommended baseline monitoring, and no patients received all recommended monitoring in any of the follow-up years (Table 2). The highest numerical rates of both baseline and follow-up monitoring were for weight and blood pressure. Baseline and follow-up rates of lipid and glucose were low. Twenty-eight (70.0%) and 17 (42.5%) patients had at least 1 SGA dispensing during years 2 and 3, respectively (Table 3). At least one MAE was identified in 14/40 patients during year 1, 5/28 patients during year 2, and 2/17 patients during year 3 (Table 3). The most frequent MAE identified was weight gain during years 1, 2, and 3. Among patients identified with a least 1 MAE, 4/14, 2/5, and 2/2 received a behavioral intervention during years 1, 2, and 3, respectively. Thirty-six of 40, 22/28, and 16/17 patients had at least 1 inpatient stay or emergency department visit, and 13/40, 9/28, and 6/17 patients had an interchange to another SGA during years 1, 2, and 3, respectively (Table 3).

TABLE 2: 

Metabolic monitoring at baseline and by study year

Metabolic monitoring at baseline and by study year
Metabolic monitoring at baseline and by study year
TABLE 3: 

Medication and health services use, metabolic outcomes, and behavioral interventions by study year

Medication and health services use, metabolic outcomes, and behavioral interventions by study year
Medication and health services use, metabolic outcomes, and behavioral interventions by study year

Our retrospective cohort analysis of 40 IHCDS patients identified that children ≤5 years of age newly initiated on an SGA rarely received recommended baseline or follow-up metabolic monitoring. Although we found low rates of overall monitoring, weight and blood pressure monitoring were performed most often. The findings from our study are important as they add to the knowledge of SGA use in very young children who are not Medicaid beneficiaries.

The observed low rates of laboratory monitoring are similar to that reported in other settings. A study9  of Medicaid-enrolled children who initiated an SGA identified that only 31% and 14% received glucose and lipid tests, respectively. Honey and colleagues18  identified that 32 adolescent patients in a pediatric clinic received an SGA with only 13% receiving baseline monitoring.

Metabolic monitoring is a recognized challenge in young patients; collecting fasting laboratory samples can be difficult due to school schedules and parental work commitments.18,19  In addition, patient and family understanding of SGA-associated risks and the need for monitoring may affect patient decisions to comply with laboratory monitoring. Parents may be reluctant to have monitoring performed that involves a needle-stick due to the potential for patient trauma, particularly in patients with autism. Consequently, there may be a similar hesitancy by prescribing providers to order laboratory monitoring. In a national survey20  of child and adolescent psychiatrists, physicians were less likely to perform metabolic monitoring if they perceived a low metabolic risk with the SGA or expected poor adherence to laboratory monitoring.

In our study, 35% of patients experienced a MAE during year 1, followed by approximately 18% and 12% of patients in years 2 and 3, respectively. Most patients experienced weight gain, and 1 patient had elevated triglycerides. Although some of our patients were only prescribed an SGA for <1 year, MAEs, primarily weight gain, can occur within a short time frame after initiation,7  and children and adolescents may be at greater risk for unhealthy weight gain with SGA use than adults.21  This may be due to drug metabolism differences and lack of development in the prefrontal cortex, leading to dysregulation of the hypothalamus and, thus, increased caloric intake. Caution is warranted as weight gain and abnormal metabolic status in childhood are associated with poor cardiovascular outcomes in adulthood.22,23 

In our study, we identified that a number of patients with an MAE received a behavioral intervention. Appropriate strategies to minimize metabolic complications include lifestyle interventions and reevaluation of SGA use if a mild MAE occurs. Discontinuing SGA, decreasing to the lowest dose, or interchange to another agent should be considered if a severe MAE occurs.17  We identified that a large majority of the patients in our study had at least 1 mental health encounter during every year of follow-up. This finding is in contrast to Olfson and colleagues6  who reported that only approximately 40% of the very young patients in their study had a mental health encounter. Conversely, we identified numerically larger proportions of patients with an inpatient stay/emergency department visit during follow-up than Olfson and colleagues6  (≈25% versus ≈5%). This discrepancy is likely because Olfson and colleagues reported only mental health–related stays/visits and we reported all-cause stays/visits.

Implications for Providers

The expanded use of SGAs to younger children and the associated risk of adverse health outcomes have led to increased national attention. Quality measures pertaining to SGA use in young children have been developed. For example, the Pharmacy Quality Alliance's Antipsychotic Use in Children under Five Years Old addresses the percentage of children <5 years of age who receive an off-label prescription for an SGA.1  This measure is designed to assess the number of children with ≥1 prescription for an SGA with a cumulative days' supply ≥30 days. Multiple stakeholders have commented that the increasing use of SGAs in children is concerning due to safety risks; thus, the implementation of quality measures may reduce gaps in care and ensure prudent SGA use.16 

Although this study identified that recommended SGA metabolic monitoring in children ≤5 years of age is limited and MAEs were found in such patients who did have monitoring, many questions remain. For instance, what are the consequences of long-term SGA use that are not approved for or well-studied in this age group? Who should be responsible for ensuring monitoring—is this on the provider, parent, or insurer? Future studies should examine these critical questions.

Limitations

Although this study provides important information on SGA use in very young patients, it was limited by a lack of information surrounding family understanding of SGA risks and use of shared decision-making processes. Thus, we were unable to assess if a patient's family chose not to receive metabolic monitoring. In addition, we were unable to assess provider factors or other barriers to monitoring, including lab monitoring that had been ordered but not obtained. We also acknowledge that several changes occurred in practice standards and treatment options during the study time frame. For example, risperidone was approved for the treatment of irritability associated with autism in children 5 years and older in 2006, making it the first FDA-approved SGA available for use in children. Only 12.5% of our study patients were initiated on a SGA prior to this time. Furthermore, we had a small sample size; however, there is little information on SGA use published in this patient population, so our results may help to elucidate trends of SGA use and monitoring in pediatrics from an IHCDS. Last, although prescription refills could be assessed, we were unable to determine if patients actually ingested their prescribed medication.

Baseline and follow-up recommended metabolic monitoring was poor in an IHCDS population of children ≤5 years of age who were newly initiated on an SGA. Among patients identified with an MAE, behavioral interventions were common. Future studies should focus on examining barriers to monitoring in order to improve health care quality.

This study was funded by the Kaiser Permanente Colorado Pharmacy Department. Additional support provided by an American College of Clinical Pharmacy Ambulatory PRN Grant.

1
Pharmacy Quality Alliance [Internet]
.
Technical specifications for PQA approved measures
.
Springfield, VA: 2014 [updated 2014 Jul; cited 2016 Jun 14].
2
Olfson
M,
Crystal
S,
Huang
C,
Gerhard
T.
Trends in antipsychotic drug use by very young, privately insured children
.
J Am Acad Child Adolesc Psychiatry
.
2013
;
49
(
1
):
13
-
23
.
PubMed PMID: 20215922
.
3
Second Generation Antipsychotic Use Among Medicaid-Enrolled Children: Quality-of-Care Concerns [Internet]
.
OEI-07-12-00320. Department of Health and Human Services [updated Mar 2015; cited 2016 May 26]
.
4
Rubin
D,
Matone
M,
Huang
Y-S,
dosReis S, Feudtner C, Localio R. Interstate variation in trends of psychotropic medication use among Medicaid-enrolled children in foster care
.
Child Youth Serv Rev
.
2012
;
34
(
8
):
1492
-
9
. DOI: .
5
Administration for Children and Families: Promoting the Safe, Appropriate, and Effective Use of Psychotropic Medication for Children in Foster Care [Internet]
.
Log no. ACYF-CB-IM-12-03. Department of Health and Human Services [updated 2012 Apr 11; cited 2016 May 26]
.
6
American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity
.
Consensus development conference on antipsychotic drugs and obesity and diabetes
.
Diabetes Care
.
2004
;
27
(
2
):
596
-
601
.
PubMed PMID: 14747245
.
7
Correll
CU,
Manu
P,
Olshanskiy
V,
Napolitano
B,
Kane
JM,
Malhotra
AK.
Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents
.
JAMA
.
2009
;
302
(
16
):
1765
-
73
. DOI: . PubMed PMID: 19861668; PubMed Central PMCID: PMC3055794.
8
Vitiello
B,
Correll
C,
van Zwieten-Boot
B,
Zuddas
A,
Parellada
M,
Arango
C.
Antipsychotics in children and adolescents: increasing use, evidence for efficacy and safety concerns
.
European Neuropsychopharmacol
.
2009
;
19
(
9
):
629
-
35
. DOI: . PubMed PMID: 19467582.
9
Morrato
EH,
Nicol
GE,
Maahs
D,
Druss
BG,
Hartung
DM,
Valuck
RJ,
et al.
Metabolic screening in children receiving antipsychotic drug treatment
.
Arch Pediatr Adolesc Med
.
2010
;
164
(
4
):
344
-
51
. DOI: . PubMed PMID: 20368487.
10
Galling
B,
Roldán
A,
Nielsen
RE,
Nielsen
J,
Gerhard
T,
Carbon
M,
et al.
Type 2 diabetes mellitus in youth exposed to antipsychotics
.
JAMA Psychiatry
.
2016
;
73
(
3
):
247
-
59
. DOI: . PubMed PMID: 26792761.
11
Correll
C.
Antipsychotic use in children and adolescents: Minimizing adverse events to maximize outcomes
.
J Am Acad Child Adolesc Psychiatry
.
2008
;
47
(
1
):
9
-
20
. DOI: . PubMed PMID: 18174821.
12
Pringsheim
T,
Lam
D,
Ching
H,
Patten S.
Metabolic
and neurological complications of second-generation antipsychotic use in children
.
Drug Saf
.
2011
;
34
(
8
):
651
-
68
. DOI: . PubMed PMID: 21751826.
13
Hasnain
M,
Vieweg
WVR,
Fredrickson
SK,
Beatty-Brooks
M,
Fernandez
A,
Pandurangi
AK.
Clinical monitoring and management of the metabolic syndrome in patients receiving atypical antipsychotic medications
.
Prim Care Diabetes
.
2009
;
3
(
1
):
5
-
15
. DOI: . PubMed PMID: 19083283.
14
Delate
T,
Kauffman
YS,
Botts
SR,
Wong
C,
Gaughan
KM.
Metabolic monitoring in commercially insured pediatric patients newly initiated to take a second-generation antipsychotic
.
JAMA Pediatr
.
2014
;
168
(
7
):
679
-
81
. DOI: . PubMed PMID: 24796974.
15
Paradise
J,
Garfield
R.
What is Medicaid's impact on access to care, health outcomes, and quality of care? [Internet]
.
Kaiser Family Foundation [updated 2013 Aug 2; cited 2016 May 26]
. .
16
National Committee for Quality Assurance
.
Safe and judicious antipsychotic use in children and adolescents [Internet]
.
National Committee for Quality Assurance [updated 2014 March 19; cited 2016 May 26]
.
17
Ho
J,
Panagiotopoulos
C,
McCrindle
B,
Grisaru
S,
Pringsheim
T;
Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children (CAMESA) guideline group. Management recommendations for metabolic complications associated with second generation antipsychotic use in children and youth
.
J Can Acad Child Adolesc Psychiatry
.
2011
;
20
(
3
):
234
-
41
.
PubMed PMID: 21804854
.
18
Honey
BL,
Ramos
L,
Brahm
NC.
Evaluation of monitoring for metabolic effects in children treated with second generation antipsychotics in a pediatric clinic
.
J Pediatr Pharmacol Ther
.
2013
;
18
(
4
):
292
-
7
. DOI: . PubMed PMID: 24719589.
19
Krill
RA,
Kumra
S.
Metabolic consequences of second-generation antipsychotics in youth: appropriate monitoring and clinical management
.
Adolesc Health Med Ther
.
2014
;
5
:
171
-
82
. DOI: . PubMed PMID: 25298741.
20
Rodday
AM,
Parsons
SK,
Mankiw
C,
Correll
CU,
Robb
AS,
Zima
BT,
et al.
Child and adolescent psychiatrists' reported monitoring behaviors for second-generation antipsychotics
.
J Child Adolesc Psychopharmacol
.
2015
;
25
(
4
):
351
-
61
. DOI: . PubMed PMID: 25918843.
21
Sikich
L,
Frazier
JA,
McClellan
J,
Findling
RL,
Vitiello
B,
Ritz
L,
et al.
Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study
.
Am J Psychiatry
.
2008
;
165
(
11
):
1420
-
31
. DOI: . PubMed PMID: 18794207.
22
Baker
JL,
Olsen
LW,
Sørensen
TI.
Childhood body-mass index and the risk of coronary heart disease in adulthood
.
N Engl J Med
.
2007
;
357
(
23
):
2329
-
37
. DOI: . PubMed PMID: 18057335.
23
Srinivasan
SR,
Myers
L,
Berenson
GS.
Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: the Bogalusa Heart Study
.
Diabetes
.
2002
;
51
(
1
):
204
-
9
.
PubMed PMID: 11756342
.

Competing Interests

Disclosures: The authors have no conflicts of interest to disclose.