• Research Article
  • |
  • Open Access

Metabolic adverse events associated with antipsychotic polypharmacy versus monotherapy among new pediatric users

  • Arpit Kashyap;
    • Harvard Pilgrim Health Care, USA
  • Bradley C Martin;
    • Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences, USA
  • Dinesh Mittal;
    • G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS, USA and University of Mississippi Medical Center, Jackson, MS, USA
  • Chenghui Li
    • Division of Pharmaceutical Evaluation and Policy, University of Arkansas for Medical Sciences, USA

  • Corresponding Author(s): Chenghui Li

  • Associate Professor, Division of Pharmaceutical Evaluation and Policy, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 W. Markham, slot 522, Little Rock, AR 72205, USA

  • cli@uams.edu

  • + (501)-686-6298

  • Li C (2018).

  • This Article is distributed under the terms of Creative Commons Attribution 4.0 International License

Received : Feb 27, 2018
Accepted : May 07, 2018
Published Online : May 10, 2018
Journal : Annals of Epidemiology and Public health
Publisher : MedDocs Publishers LLC
Online edition : http://meddocsonline.org

Cite this article: Kashyap A, Martin BC, Mittal D, Li C. Metabolic adverse events associated with antipsychotic polypharmacy versus monotherapy among new pediatric users. A Epidemiol Public Health. 2018; 1: 1003.

Abstract

Purpose: Limited information is available on antipsychotic polypharmacy and associated metabolic adverse events in a pediatric population. This study sought to determine the risk of metabolic adverse events associated with antipsychotic polypharmacy compared to antipsychotic monotherapy use among commercially insured pediatric antipsychotic users.

Methods: This was a retrospective cohort study of commercial health plans claims data. New users of antipsychotic medication(s) aged 1-17 years on the date of the first antipsychotic prescription were selected and followed for up to one year after antipsychotic initiation. Patients with preexisting metabolic conditions were excluded. Antipsychotic polypharmacy was defined as concurrent use of two or more chemically distinctive antipsychotic agents. Metabolic adverse events were captured using diagnosis or medication use during the one-year post-index period. Survival analyses using Cox regression models with time-varying exposure variables (any antipsychotic use, antipsychotic dose, antipsychotic exposure-dose combination and antipsychotic type) were conducted adjusting for baseline patient demographic and clinical characteristics.

Results: The study included 3,038 pediatric patients with antipsychotic use and 11.06% of them received antipsychotic polypharmacy during the one-year follow-up period. Compared to monotherapy, no statistically significant effect of antipsychotic polypharmacy was found for metabolic adverse events However, high total daily dose of antipsychotics was found to be significantly associated with metabolic adverse events (HR: 2.42 CI: 1.35-4.32).

Conclusion: Although no clear increase in risk of metabolic adverse events were detected for antipsychotic polypharmacy use compared to monotherapy, high daily dose of total antipsychotic use was associated with elevated risk for metabolic adverse events in pediatric patients.

Keywords: Antipsychotics; Polypharmacy; Metabolic outcomes; Pediatrics; Retrospective

Introduction

      Despite the limited indications, antipsychotics are increasingly used in pediatric populations [1,2]. From 1995 to 2005, children under 18 who used antipsychotics increased eight fold from 0.3 million in 1995 to 2.4 million in 2005 [1]. Second Generation Antipsychotics (SGAs) have gained wide popularity in the pediatric population in recent times [3], accounting for 92.3% of antipsychotic medications prescribed among youths between 2000 and 2002 [2].

      More concerning is that 3-27% of children and adolescents in the US were treated with antipsychotic polypharmacy, although the estimates vary by the definition used, study population, and clinical setting [4-6]. This is alarming because existing randomized clinical trials [7-15] do not show clear evidence of a beneficial effect of antipsychotic polypharmacy compared to monotherapy except for augmentation of clozapine in antipsychotic monotherapy treatment resistant patients [16,17]. Consistent with this lack of evidence for efficacy, treatment guidelines either do not recommend use of antipsychotic polypharmacy or limit its use to patients with refractory schizophrenia for short periods of time [18-21]. A large proportion of multiple antipsychotic use comprises of two or more SGAs or a SGA plus a First Generation Antipsychotic (FGA) [2,6]. Significant adverse metabolic side effects have been reported in adults and children with the use of antipsychotics, especially with the use of SGAs [3,22]. Compared with adults, children and adolescents appear to be at greater risk of weight gain and metabolic abnormalities when using antipsychotics [23].

      Although studies have examined antipsychotic use in the pediatric population [24-30] data on the metabolic adverse events associated with antipsychotic polypharmacy use is limited for pediatrics. In a few observational studies that examined the safety of antipsychotics use in children, the risk of metabolic side effects appeared to increase with multiple antipsychotics use [6,31].

      This study addressed the gaps in knowledge and aimed to compare the risk of metabolic adverse events between antipsychotic polypharmacy and antipsychotic monotherapy in a sample of pediatric population obtained from a large national commercially insured population.

      Exposure to antipsychotics as well as the intensity of exposure defined by antipsychotic dose and the type of antipsychotic agents (SGA vs. FGA) were examined, all of which were defined as time-varying variables to account for changes in exposure during the one year follow-up period after initiation. We hypothesized that antipsychotic polypharmacy use would be associated with increased risk of metabolic adverse events compared to monotherapy.

Methods

Study design and data source

      A retrospective cohort design was used. This study utilized a 10% random sample of the PharMetrics Patient-Centric Database (IMS’ LifeLinkTM Health Plan Claims data obtained from PharMetrics Inc., Watertown, MA), derived from insurance claims of over 98 managed care plans all across United States for over 61 million unique patients. Data from July 1, 1999 to December 31, 2009 were used in this study.

Patient selection

      The study population consisted of new users of antipsychotic medications aged 1-17 years on the date of the first antipsychotic use (“index date”) between January 1, 2000 and December 31, 2008. A “new user” was defined as an incident antipsychotic user with no prior exposure in the 180 days before the index date (“pre-index period”) and have at least 30 days of cumulative use of any antipsychotics during the one year after the index prescription. Selected subjects must have continuous plan enrollment and pharmacy benefits from 6 months before to 12 months after the index date. A subject was followed from the index date until the occurrence of an adverse metabolic event or the end of one year post-index period (“follow-up period”), whichever occurred first. Patients with pre-existing metabolic condition(s) were excluded.

Time-varying antipsychotic use

      Antipsychotic agents were identified from pharmacy claims using GPI code 59.xx. Exposure to antipsychotic agents was checked for each day of the follow-up period. For each day, the following time-varying exposure variables were defined: any exposure (three levels: no antipsychotic use, antipsychotic monotherapy and antipsychotic polypharmacy), antipsychotic dose (three levels: no use, low dose and high dose), antipsychotic exposure-dose combination (four levels: no use, monotherapy-low dose, monotherapy- high dose and polypharmacy-any dose) and type of antipsychotic agents used (three levels: no use, FGA [with or without SGA], and SGA only). These exposure variables were examined in separate analyses.

      Daily antipsychotic exposure was defined by the number of chemically distinct antipsychotic prescriptions with days of supply covering that day. Polypharmacy use was defined as concurrent use of two chemically distinct antipsychotics on the same day. If only one antipsychotic was prescribed for that day, it was considered as monotherapy. To account for potential delayed effect of antipsychotic exposure on metabolic adverse outcomes, antipsychotic exposure time was extended to 30 days after exhausting the days of supply of each antipsychotic prescription.

      For each antipsychotic prescription, daily dose was first calculated by dividing the total dose over the days of supply of that prescription. This daily dose was assigned to each day the medication was prescribed. The total daily dose of antipsychotics was then calculated by summing up the average daily dose of all antipsychotic agents prescribed for that day for each patient. Doses of antipsychotics were converted to chlorpromazine equivalent doses, obtained from an international consensus study conducted in 2007-2008 [32]. Per the consensus guideline, the median recommended chlorpromazine dose was 600 mg/day. Based on age, the consensus recommends lowering median daily oral antipsychotic dose by 60% for children (chlorpromazine equivalent dose: 240 mg/day) and by 30% for adolescents (chlorpromazine equivalent dose: 420 mg/day). We used these median daily doses for children (age 1 – 12) and adolescents (age 13 – 17) as cut points to divide daily doses into high dose and low dose.

      For the daily exposure-dose combination, we created a timevarying variable differentiating the high and low dose monotherapy and polypharmacy use on each day. Due to limited sample size of polypharmacy use, we were not able to separately assess the risk of metabolic adverse events associated with the high and low dose polypharmacy use. Therefore, polypharmacy at any dose was compared to monotherapy-low dose, monotherapy-high dose and no use.

      In addition, given the differential risk of metabolic side effects between FGAs and SGAs, daily exposure to any FGAs (alone or with SGAs) and that to SGAs alone were also compared.

Outcome events

      The outcome events included the occurrence of metabolic adverse events during the follow-up period. These events were identified using ICD-9-CM diagnoses codes from the inpatient/ outpatient claims and medications used specifically for treatment of these conditions: Type II diabetes mellitus (250.x0-250. x2 and antidiabetic agents), obesity or abnormal weight change (278.xx, 783.1, 783.2, and antiobesity agents), dyslipidemia (272.xx and antihyperlipidemic agents). This approach has been used in other studies using claims data [33].

      Due to low incidence counts of these adverse events, particularly among polypharmacy users, individual metabolic events were not assessed separately.

Covariates

      Selection of covariates was undertaken systematically. We started with an exhaustive list of variables that may affect the metabolic outcomes and antipsychotic prescribing based on previous studies and clinical (or pharmacology) textbooks (e.g. Harrison’s Principles of Internal Medicine, 18e). The final model included only covariates that were statistically significantly associated with any polypharmacy use (>=1 day overlap in the use of >=2 antipsychotics) at P<0.05. Also, for categorical variables, at least 10 cases in each category must be present in order to be retained in the final model. Demographic characteristics and mental health-related characteristics (psychiatric disorder, psychotropic medication use and psychiatric related hospitalization) were forced to be retained in the final model regardless of their statistical significance. Demographic characteristics (age groups [1-6 years, 7-12 years, 13-15 years and 16-17 years], gender, and geographic regions [East, Mid-west, South and West]) were measured on the index date. Pre-existing psychiatric and physical health disorders were assessed during the 6-month pre-index period. Because of the significant overlap in psychiatric diagnoses and psychotropic medication use, psychiatric disorders were defined using a combination of diagnosis (Table S1 for list of ICD-9 codes) and medication use and categorized into seven categories: psychotic disorders, disruptive behavior disorder including Attention-Deficit Hyperactivity Disorder (ADHD) medications use, mood disorder including antidepressants use, pervasive developmental disorder, antianxiety and/or sedatives use, mood stabilizers, and other mental disorders. In addition, the number of different diagnosed psychiatric disorders and the number of different psychotropic medication classes other than antipsychotics (ADHD medications, antianxiety drugs, antidepressant drugs, mood stabilizers and sedative/ hypnotics), as well as any psychiatric related hospitalizations during the 6-month pre-index period were included as proxies for the severity of mental health problems. Physical comorbidity burden was measured during the pre-index period and assessed using the Charlson comorbidity score. To control for temporal changes over time, we included indicators for the year of index antipsychotic prescription (“index-year”). Specialty of the most frequently reported provider associated with antipsychotic prescriptions during the one year post-index period was also examined.

Data analysis

      For descriptive analysis, patients with at least one day of polypharmacy use during the one-year follow-up period were compared to those without any overlapped use. Pearson Chisquare tests were used for comparisons of baseline characteristics across the two groups.

      Incident Rate Ratios (IRR) of metabolic adverse events defined as the ratio of the incident rates occurring during the antipsychotic polypharmacy time over the incidence rate during antipsychotic monotherapy time were calculated. As a descriptive analysis, we also calculated the average daily dose of antipsychotics during monotherapy exposure time and that during polypharmacy exposure time. For both analyses, antipsychotic monotherapy time was defined as the days between antipsychotic index date and the date of either antipsychotic polypharmacy initiation, first metabolic event, or the end of the one-year follow-up period, whichever occurred first. Antipsychotic polypharmacy time was calculated as the days between antipsychotic polypharmacy initiation and the date of the first metabolic event or end of the study period, whichever was earliest. If a polypharmacy user experienced an event prior to polypharmacy initiation, no antipsychotic polypharmacy time was counted for that subject. These definitions of antipsychotic monotherapy and polypharmacy exposure times are different from the time-varying exposure time defined earlier, which were used in the multivariate analyses below using time-varying exposure variables.

      Multivariate analyses using Cox’s regression models examined the association between various time-varying antipsychotic exposure measures described above and metabolic adverse events, adjusting for covariates described earlier. In all comparisons, hazard ratios were reported with no antipsychotic use as the reference group against monotherapy and polypharmacy use/exposure/dose level groups respectively. Wald tests were then used to compare polypharmacy and monotherapy use. To facilitate comparison with previous studies, unadjusted and adjusted analyses using logistic regression and Cox’s regression with time in-varying antipsychotic use variables (i.e. any polypharmacy exposure during the one-year follow-up period vs. monotherapy only use) were also conducted.

Sensitivity analysis

      To account for potential delayed effect of antipsychotic exposure, in the main analysis, we extended antipsychotic exposure time to 30 days after exhausting the days of supply of each antipsychotic prescription. Sensitivity analyses were conducted using different extension windows (0 days [i.e. no time considered exposed beyond prescription supply], 7 days, or 60 days) after exhaustion of each antipsychotic prescription. In the most liberal definition to define polypharmacy exposure, once a person had a day of overlapped use of two or more antipsychotics, all subsequent days were considered as days for polypharmacy use.

      For antipsychotic dose, we conducted sensitivity analysis to assess potential delayed effect of antipsychotic dose on adverse events by extending the total daily dose beyond 30 days. The dosing extension windows were hierarchically applied with highdose extends over the subsequent days with no or low-dose use and low-dose use over no dose days. For instance, days with high-dose exposure will not be affected by the extended dose from a previous prescription. However, for days with low-dose or no exposure, if the previous prescription within 30 days was of high dose, these days were recorded as high-dose exposure days as a result of this extension.

      Since polypharmacy use for a short period could represent a switch in therapy rather than polypharmacy, a sensitivity analysis was also conducted by excluding subjects with less than 14 days of overlapped use [34]. This analysis was repeated for all four time-varying antipsychotic use definitions.

      All statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, North Carolina). This study was approved by the Institutional Review Board of the University of Arkansas for Medical Sciences.

Results

      The study identified 3,038 new antipsychotic pediatric users and 88.9% of them used antipsychotic monotherapy throughout the follow-up period. Patients with at least one day of antipsychotic polypharmacy use were more likely to have pre-existing mood disorder (including antidepressants use) or used mood stabilizer medications in the previous 6 months. Increased antipsychotic polypharmacy was also associated with the use of two or more different classes of other psychotropic medications or having three different types of psychiatric disorders (Table 1).

table 1 Table 1

Table 1: Baseline characteristics across monotherapy and any polypharmacy treatment groups for metabolic adverse events (N=3038, events=177).

      The average daily chlorpromazine-equivalent dose was 385 mg during polypharmacy exposure time. This was nearly three times the average daily dose during low-dose monotherapy exposure time (114 mg) but 25% lower than that during high-dose monotherapy exposure time (516 mg) (Table 2).

table 2 Table 2

Table 2: Average exposure time and average daily dose of antipsychotics.

      Overall, 5.83% of patient experienced a metabolic adverse event within one year after initiation of antipsychotics. The proportion of patients that developed metabolic adverse events trended higher among polypharmacy users, although not statistically significantly different (5.66% vs 7.14% respectively, p=0.2753). Similarly, the incident rates per 1000 person-years trended higher during the polypharmacy time compared to monotherapy time, although remains statistically insignificant (IRR: 1.18; 95% CI: 0.65-1.70) (Table 3).

table 3 Table 3

Table 3: Incidence Rate Ratio for Metabolic adverse events.

      Cox-regression models with time-varying any antipsychotic exposure variable found no statistically significant effect of antipsychotic polypharmacy exposure or antipsychotic monotherapy exposure on metabolic adverse events compared to no use. Logistic regressions (unadjusted and adjusted) and Cox regression using time-invarying exposure variable found similar results (Table 4, for complete regression model results refer to supplemental tables S2-S6)

table 4 Table 4

Table 4: Incidence Rate Ratio for Metabolic adverse events.

      Cox-regression models with time-varying antipsychotic dose level showed a dose response relationship for metabolic adverse events. Compared to no use, high daily dose of antipsychotics was associated with statistically significant risk of metabolic adverse events (HR: 2.42, CI: 1.35-4.32) (Table 4). Wald test for difference between higher and lower antipsychotic doses were also statistically significant (p= 0.0197).

      Cox-regression using time-varying exposure-dose combination variable showed that the risk of metabolic adverse events nearly doubled in antipsychotic high-dose monotherapy use compared to non-exposure (HR: 2.34, CI 1.26-4.36) (Table 4). Polypharmacy use regardless of dose has an equally high hazard of experiencing metabolic side effect compared to no use, although not statistically significant (HR=2.34, CI: 0.85-6.46). Wald test comparing polypharmacy-any dose and high-dose monotherapy shows no statistically significant difference (p=0.9986). However, statistically significant difference for metabolic outcomes were found between low-dose monotherapy compared to high-dose monotherapy (Wald test, p=0.0347).

      No statistically significant effect of exposure to FGA (alone or in combination with SGAs) and SGA only were observed for metabolic adverse events (Table 4).

      Sensitivity analyses using different extension windows for antipsychotic exposure (0 day, 7 days, 60 days, or the most liberal definition where the time after initiation of antipsychotic polypharmacy use were all attributed to polypharmacy use) or excluding patients with less than 14 days of overlapped use did not materially affect the findings. (Supplemental Tables S2-S6).

      Several other factors were statistically significantly associated with metabolic adverse events. Age groups 1-6 years (HR: 0.39, CI: 0.17-0.90) and 7-12 years (OR: 0.63, CI: 0.42-0.97), and western region (HR: 0.55, CI: 0.31-0.97) were associated with lower risk of metabolic adverse events compared to 16-17 years and mid-west region respectively (Supplemental Table S4).

Discussion

      In this study of commercially insured new antipsychotic pediatric users, we found no evidence of differential metabolic adverse events between antipsychotic monotherapy and polypharmacy use. However, risk of metabolic adverse events was found to increase with high daily doses of antipsychotics.

      The crude incidence rate of metabolic adverse events was found to be 5.83% within one year of antipsychotic initiation, which was similar to those reported in other studies [6,31]. However, the adjusted hazard ratios of developing metabolic adverse events during monotherapy and polypharmacy exposure time were not statistically significant, but trended towards an increased risk with polypharmacy use.

      Previous studies assessing the risk of metabolic adverse events associated with antipsychotic polypharmacy use in pediatric patients were scarce. Two studies of pediatric populations found use of multiple antipsychotics was associated with elevated risk of Type II diabetes, dyslipidemia and weight gain [6,31]. However, differences in study design and analytical methodology prevent a direct comparison with our study: different study populations (Medicaid vs. commercially insured population in our study), different definitions of antipsychotic polypharmacy use (multiple antipsychotics use including both sequential use and concurrent use vs. only overlapped use of two or more antipsychotic agents in our study), nonusers of any psychotropic agents as control groups in their studies. More importantly, unlike previous studies, we defined antipsychotic polypharmacy and monotherapy exposure as time-varying variables to account for changes in antipsychotics use over time. To allow comparison with other studies, we also defined antipsychotic exposure as time-invarying variables but still did not find statistically significant effects of polypharmacy. Larger studies of pediatric populations are needed to confirm our findings.

      We found a dose effect antipsychotic exposure on metabolic adverse events. However, this appeared to be mostly attributed to high-dose antipsychotic monotherapy use, which was found to be associated with increased risk of metabolic adverse events compared to no exposure. In this study, the average daily antipsychotics dose prescribed during low-dose and high-dose polypharmacy exposure time were both higher, but did not double the average daily dose during low-dose and high-dose monotherapy exposure time respectively. This finding is consistent with previous literature [35-37] and suggests that polypharmacy may have been employed to reduce the risk of side effect(s) of any individual antipsychotic agents involved by using multiple antipsychotics at lower individual doses [17,38].

      Results of this study should be interpreted while considering the following limitations. Due to small sample size, we defined antipsychotic polypharmacy as the use of two or more antipsychotic agents for at least one day. This approach may have included titration period when switching one antipsychotic to another. However, sensitivity analysis by excluding patients with less than 14 days of overlapped use found similar results. The exact duration for the delayed effect of antipsychotic exposure was unknown. We extended the antipsychotic exposure to 30- day post prescription supply in our main analysis but conducted sensitivity analysis with different extension windows and the results were largely consistent. The sample was extracted from a large commercially insured population and therefore the results may not generalize to other pediatric populations or other insurance setting. Outcome events were ascertained based on diagnoses codes or medication use in the medical and pharmacy claims, which are prone to coding errors and misclassification and may understate the metabolic adverse events in our study. Moreover, no details on the inpatient medication use were available, which may have led to underestimation of medication use and potentially antipsychotic polypharmacy use. Pharmacy claims report prescription fills which do not necessarily translate into actual patient use. Additionally, the insurance claims data lacked information on lifestyle factors, race/ ethnicity, rural/urban place of residence and genetic composition which may have caused omitted variable bias. Due to the observational study design, these results were only indicative of association between exposure and outcome, if any, and cannot ascertain the direction of causality.

      In conclusion, although no increase in the risk of metabolic adverse events was detected with the use of antipsychotic polypharmacy, using high daily doses of antipsychotics was associated with elevated risk for metabolic adverse events. This finding was applicable to both monotherapy and polypharmacy use.

Acknowledgements

      The use of IMS LifeLink Health Plans data was supported by University of Arkansas Translation Research Institute (National Institute of Health [NIH] Grant #1UL1RR029884).

References

  1. Alexander GC, Gallagher SA, Mascola A, Moloney RM, Stafford RS. Increasing off-label use of antipsychotic medications in the United States, 1995-2008. Pharmacoepidemiol Drug Saf. 2011; 20: 177-184.
  2. Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry. 2006; 63: 679-685.
  3. Constantine RJ, Boaz T, Tandon R. Antipsychotic polypharmacy in the treatment of children and adolescents in the fee-for-service component of a large state Medicaid program.
  4. Toteja N, Gallego JA, Saito E, Gerhard T, Winterstein A, Olfson M, et al. Prevalence and correlates of antipsychotic polypharmacy in children and adolescents receiving antipsychotic treatment. Int J Neuropsychopharmacol. 2014; 17: 1095-1105.
  5. Morrato EH, Dodd S, Oderda G, Haxby DG, Allen R, Valuck RJ. Prevalence, utilization patterns, and predictors of antipsychotic polypharmacy: experience in a multistate Medicaid population, 1998-2003. Clin Ther. 2007; 29: 183-195.
  6. Jerrell JM, McIntyre RS. Adverse events in children and adolescents treated with antipsychotic medications. Hum Psychopharmacol. 2008; 23: 283-290.
  7. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tümüklü M, Yazici MK, Alptekin K, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005; 66: 63-72.
  8. Canuso CM, Dirks B, Carothers J, Kosik-Gonzalez C, Bossie CA, Zhu Y, et al. Randomized, double-blind, placebo-controlled study of paliperidone extended-release and quetiapine in inpatients with recently exacerbated schizophrenia. Am J Psychiatry. 2009; 166: 691-701.
  9. Freudenreich O, Henderson DC, Walsh JP, Culhane MA, Goff DC. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebocontrolled trial. Schizophr Res. 2007; 92: 90-94.
  10. Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. N Engl J Med. 2006; 354: 472-482.
  11. Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, doubleblind, placebo-controlled trial. Am J Psychiatry. 2005; 162: 130-136.
  12. Kotler M, Strous RD, Reznik I, Shwartz S, Weizman A, Spivak B. Sulpiride augmentation of olanzapine in the management of treatment-resistant chronic schizophrenia: evidence for improvement of mood symptomatology. Int Clin Psychopharmacol. 2004; 19: 23-26.
  13. Potkin SG, Thyrum PT, Alva G, Bera R, Yeh C, Arvanitis LA. The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine. J Clin Psychopharmacol. 2002; 22: 121-130.
  14. Shiloh R, Zemishlany Z, Aizenberg D, Radwan M, Schwartz B, Dorfman-Etrog P, et al. Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study. Br J Psychiatry. 1997; 171: 569-573.
  15. Shim JC, Shin JG, Kelly DL, Jung DU, Seo YS, Liu KH, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry. 2007; 164: 1404-1410.
  16. Goren JL, Parks JJ, Ghinassi FA, Milton CG, Oldham JM, Hernandez P, et al. When is antipsychotic polypharmacy supported by research evidence? Implications for QI. Jt Comm J Qual Patient Saf. 2008; 34: 571-582.
  17. Miller AL, Craig CS. Combination antipsychotics: pros, cons, and questions. Schizophr Bull. 2002; 28: 105-109.
  18. Treatment of schizophrenia 1999. The expert consensus guideline series. J Clin Psychiatry. 1999; 60: 3-80.
  19. . Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010; 36: 94-103.
  20. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161: 1-56.
  21. Moore TA, Buchanan RW, Buckley PF, Chiles JA, Conley RR, Crismon ML, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007; 68: 1751-1762.
  22. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry. 2008; 47: 9-20.
  23. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006; 45: 771-791.
  24. Haas M, Eerdekens M, Kushner S, Singer J, Augustyns I, Quiroz J, et al. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study. Br J Psychiatry. 2009; 194: 158-164.
  25. Haas M, Unis AS, Armenteros J, Copenhaver MD, Quiroz JA, Kushner SF. A 6-week, randomized, double-blind, placebo-controlled study of the efficacy and safety of risperidone in adolescents with schizophrenia. J Child Adolesc Psychopharmacol. 2009; 19: 611-621.
  26. Kumra S, Frazier JA, Jacobsen LK, McKenna K, Gordon CT, Lenane MC, et al. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. 1996; 53: 1090-1097.
  27. Kumra S, Kranzler H, Gerbino-Rosen G, Kester HM, De Thomas C, Kafantaris V, et al. Clozapine and “high-dose” olanzapine in refractory early-onset schizophrenia: a 12- week randomized and double-blind comparison. Biol Psychiatry. 2008; 63: 524-529.
  28. Shaw P, Sporn A, Gogtay N, Overman GP, Greenstein D, Gochman P, et al. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry. 2006; 63: 721-730.
  29. Sikich L, Hamer RM, Bashford RA, Sheitman BB, Lieberman JA. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology. 2004; 29: 133-145.
  30. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, et al. Double-blind comparison of first- and secondgeneration 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: 1420-1431.
  31. McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsychotic treatment in children and adolescents. Arch Pediatr Adolesc Med. 2008; 162: 929-935.
  32. Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010; 167: 686-693.
  33. Andrade SE, Lo JC, Roblin D, Fouayzi H, Connor DF, Penfold RB, et al. Antipsychotic medication use among children and risk of diabetes mellitus. Pediatrics. 2011; 128: 1135- 1141.
  34. Ganguly R, Kotzan JA, Miller LS, Kennedy K, Martin BC. Prevalence, trends, and factors associated with antipsychotic polypharmacy among Medicaid-eligible schizophrenia patients, 1998-2000. J Clin Psychiatry. 2004; 65: 1377-1388.
  35. Barbui C, Nose M, Mazzi MA, Thornicroft G, Schene A, Becker T, et al. Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries. Int Clin Psychopharmacol. 2006; 21: 355-362.
  36. Lochmann van Bennekom MW, Gijsman HJ, Zitman FG. Antipsychotic polypharmacy in psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost effectiveness. J Psychopharmacol. 2013; 27: 327-336.
  37. . Ranceva N, Ashraf W, Odelola D. Antipsychotic polypharmacy in outpatients at Birch Hill Hospital: incidence and adherence to guidelines. J Clin Pharmacol. 2010; 50: 699- 704.
  38. Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand. 2002; 106: 323- 330.

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