sign in sign up
<<
Home , Acetophenazine, Bromperidol, Butaperazine, Carfenazine, Clopenthixol, Clopimozide

Diabetes Care 1

Angela Galler,1 Esther Bollow,2

Comparison of Glycemic and CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL CLIN Michael Meusers,3 Bela Bartus,4 Metabolic Control in Youth Andrea Nake,¨ 5 Holger Haberland,6 Edith Schober,7 and Reinhard W. Holl,2 for With Type 1 Diabetes With the German Federal Ministry for Education and Research (BMBF) Competence and Without Network of Diabetes Mellitus : Analysis From the Nationwide German/Austrian Diabetes Survey (DPV)

DOI: 10.2337/dc14-2538

OBJECTIVE The objective of this study was to explore metabolic risk factors and glycemic control in youth with type 1 diabetes treated with typical or atypical .

RESEARCH DESIGN AND METHODS Data for 60,162 subjects with type 1 diabetes up to the age of 25 years registered in the nationwide German/Austrian Diabetes Survey were included in the analy- sis. BMI; HbA1c; treatment strategy; prevalence of hypertension, dyslipidemia, microalbuminuria, and retinopathy; frequency of hypoglycemia and diabetic ketoacidosis (DKA); and immigrant status among subjects treated with typical 1Charite´dUniversitatsmedizin¨ Berlin, Paediatric or atypical antipsychotics were compared with those without antipsychotic med- Endocrinology and Diabetology, University Hospital for Children and Adolescents, Campus ication and analyzed by regression analysis. Virchow Klinikum, Berlin, Germany 2Institute of Epidemiology and Medical Biometry, RESULTS University of Ulm, Ulm, Germany A total of 291 subjects with type 1 diabetes (median diabetes duration 7.2 years) 3Gemeinschaftskrankenhaus Herdecke, Child and Adolescent Psychiatry, Herdecke, Germany received antipsychotic (most commonly ). Subjects trea- 4 P Filderklinik Paediatrics, Filderstadt, Germany ted with antipsychotics had a higher BMI ( = 0.004) and dyslipidemia was more 5University Carl Gustav Carus Dresden, University frequent (P = 0.045) compared with subjects not receiving antipsychotic medica- Hospital for Children and Adolescents, Dresden, tion. Frequencies of severe hypoglycemia and DKA were significantly higher in Germany 6 subjects receiving antipsychotics (P < 0.001). The prevalences of hypertension, Sana Hospital Berlin Lichtenberg, Hospital for Children and Adolescents, Berlin, Germany microalbuminuria, and retinopathy were not different. In subjects treated with 7Medical University Vienna, University Hospital typical antipsychotics, glycemic control did not differ compared with those who for Children and Adolescents, Vienna, Austria did not receive antipsychotic medications. By contrast, subjects treated with Corresponding author: Angela Galler, angela atypical antipsychotics had higher HbA1c levels (P = 0.022). [email protected]. Received 25 October 2014 and accepted 25 Conclusions February 2015. This analysis from a real-life survey demonstrated that subjects with antipsychotic This article contains Supplementary Data online medication had worse glycemic control and a higher rate of acute complications at http://care.diabetesjournals.org/lookup/ compared with those without antipsychotic medication. Health care teams caring suppl/doi:10.2337/dc14-2538/-/DC1. for youth with type 1 diabetes taking antipsychotic medication need to know © 2015 by the American Diabetes Association. Readers may use this article as long as the work about these findings. We suggest monitoring metabolic risk factors as well as is properly cited, the use is educational and not providing diabetes education about prevention of acute complications. for profit, and the work is not altered. Diabetes Care Publish Ahead of Print, published online March 17, 2015 2 Type 1 Diabetes and Antipsychotic Medication Diabetes Care

Over the past two decades the use of diabetes treated with atypical or typical ISPAD and American Diabetes Association antipsychotic in medical practice antipsychotics in a real-life setting. guidelines (21). Albuminuria was screened has increased in the U.S. and in Europe according to ISPAD and the German Dia- (1–7). In the pediatric, adolescent, and RESEARCH DESIGN AND METHODS betes Association guidelines (21,22). Albu- young adult populations, antipsychotics The German and Austrian Diabetes Sur- min and creatinine were measured by are primarily used for treatment of psy- vey (DPV) is a prospective, nationwide center-specific laboratory methods that chiatric disorders, mainly , documentation of subjects with type 1 had to meet German internal and external and for concomitant treatment of bipo- diabetes. Demographic, anthropometric, quality requirements for laboratory anal- lar and affective disorders. In clinical and diabetes-related data of subjects ysis, according to the guidelines of the practice antipsychotics also are used for with type 1 diabetes are recorded in German Medical Association (23). Micro- the treatment of symptoms related to 391 diabetes care centers in Germany albuminuria was defined as an albumin behavior and of nonpsychotic disorders, and Austria. All data were derived from excretion rate $20mg/min or urine for example, in obsessive-compulsive hospital charts or were specifically asked albumin-to-creatinine ratio $2.5 mg/mmol. disorders, personality disorders, Tourette for by health professionals. No self-report Macroalbuminuria was defined as syndrome, and autism (1–7). questionnaires were used. The ethics albumin excretion rate $ 200 mg/min Treatment with antipsychotics may committee of Ulm University approved or a urine albumin-to-creatinine ratio result in serious adverse effects. In ad- data collection and anonymous analysis $35 mg/mmol (21,24). Serum concen- dition to the for study purposes. Overall, data from trations of cholesterol, HDL, and LDL caused by typical antipsychotics, the ad- 83,748 subjects with type 1 diabetes were measured. Dyslipidemia was diag- verse metabolic effects of atypical anti- were registered in the survey from 1995 nosed if at least one lipid parameter was psychotics are of concern (8–14). The until March 2013. A total of 60,162 chil- increased (cutoff levels of .200 mg/dL use of atypical antipsychotics may result dren, adolescents, and adults (up to the for total cholesterol, .130 mg/dL for in weight gain, changes in lipid concen- age of 25 years) with type 1 diabetes and LDL, and ,35 mg/dL for HDL) and if trations, increased glucose concentra- with a diabetes duration of more than at least two of three consecutive mea- tions, and insulin resistance in healthy 6 months were included in this analysis. surements were above the cutoff subjects (8–14). Weight gain occurs in Clinical characteristics and laboratory levels. Immigration status was defined up to 50% of patients receiving long- parameters were assessed; BMI and as the place of birth of one or both term treatment for schizophrenia (8). blood pressure were recorded, and parents in a country other than Germany Several studies indicate that weight age-specific normal values were ob- or Austria. gain with antipsychotic medication is tained from current guidelines (16–18). Subjects taking antipsychotic medica- more severe in children and adolescents BMI SD score (SDS) was calculated using tions were identified. Antipsychotic compared with adults (8). One study of national reference data in Germany agents (neuroleptics) were classified as children encountered a 10% increase in (16). Hypertension was defined accord- either atypical antipsychotics or typical body weight after 3 months of treat- ing to the Second Task Force on Blood antipsychotics (Table 1). Duration of an- ment with (15). Further- Pressure Control in Children and Adoles- tipsychotic medication use was assessed. more, adults and youths taking atypical cents (17,18). Furthermore, treatment antipsychotics have an increased risk of strategy (multiple daily injections or in- Statistical Analysis developing type 2 diabetes (6,13,14). sulin pump treatment); frequency of We used SAS statistic software version Weight gain and changes in metabolic severe hypoglycemia (hypoglycemia 9.3 for data evaluation and statistical parameters also have been described with a loss of consciousness or seizure); analysis. Data are presented as medians for treatment with some typical antipsy- frequency of episodes of diabetic ketoa- and interquartile ranges or as means chotic agents. Interpretation of these cidosis (DKA; pH ,7.30, defined accord- and 95% upper and lower confidence effects is more difficult because of the ing to International Society for Pediatric limits, as appropriate. Prevalences and inadequate evaluation of confounding and Adolescent Diabetes [ISPAD] guide- frequencies of complications are pre- factors in many early studies of typical lines) (19); and frequency of hospital ad- sented as either percentages or as event antipsychotics (8). missions were assessed. Rates of severe rates per 1 patient-year. The Kruskal- Because of the adverse metabolic ef- hypoglycemia, rates of DKA, and fre- Wallis test was performed to compare fects of antipsychotics, patients with quency of hospital admissions were as- age, diabetes duration, BMI SDS, and type 1 diabetes, who already are at risk sessed during the previous year and median HbA1c in subjects with or with- for an unfavorable metabolic profile, calculated and expressed per 1 patient- out treatment with typical or atypical may experience further deterioration year. Glycemic control was assessed as antipsychotics. The x2 test was used to of their metabolic risk factors with median HbA1c during the previous year. compare immigrant status, treatment antipsychotic medication. This may HbA1c was locally measured, and local strategy, frequencyofhypertension include a negative effect on glycemic HbA1c values were standardized mathe- and dyslipidemia, and frequency of ret- control and lead to a poor long-term matically to the Diabetes Control and inopathy and microalbuminuria be- prognosis in type 1 diabetes. Therefore, Complications Trial (DCCT) reference tween the groups. A t test was used to the aim of this analysis was to explore range of 4.05–6.05% (21–43 mmol/mol) compare mean BMI SDS in subjects tak- and assess metabolic risk factors and using the multiple of the mean method ing antipsychotic medication with the glycemic control in children, adoles- (20). Retinopathy and micro- or macroal- mean BMI SDS when antipsychotic med- cents, and young adults with type 1 buminuria were screened according to ication was started. A Poisson model was care.diabetesjournals.org Galler and Associates 3

Table 1—Classification of antipsychotics are shown in Table 3. Subjects with Availability in Germany/Austria type 1 diabetes treated with antipsy- Antipsychotic during period of survey chotics (60% males, 40% females; mean duration of antipsychotic medica- Typical fi : , , tion use 9.1 months) were signi cantly , , , older (17.0 vs. 15.5 years of age; P , , trifluperidol Trifluperidol available until 2005 0.001) and had a longer diabetes dura- : , tion (7.2 vs. 5.1 years; P , 0.001) (Table fluspirilene, penfluridol, Clopimozide and penfluridol not available 3) compared with subjects without anti- : , psychotic medication. The group with , , fl type 1 diabetes treated with antipsy- , uphenazine, fi , oxaflumazine, chotics comprised signi cantly more , perciazine, available until 2001; subjects with immigrant status com- (, , triflupromazine available until 2003; pared with the group without antipsy- ), , butaperazine, carfenazine, cyamemazine, chotic medication (19% vs. 13%; P = , , , oxaflumazine, perciazine, 0.003) (Table 3). Furthermore, we saw fl fl thiethylperazine, tri uoperazine, prochlorperazine, and tri uoperazine not significant differences in BMI SDS, HbA triflupromazine, available 1c levels, insulin doses, dyslipidemia, mi- : , , flupentixol, thiothixene, Clopenthixol available until 2000; croalbuminuria, rates of hypoglycemia thiothixene not available and DKA, and the rate of hospital admis- Others: , homophenazine, available since 2013; dixyrazine sion between the two groups (Table 3). loxapine and homophenazine not available However, statistical analysis showed Atypical that mean BMI SDS in subjects with an- Available since 1974 tipsychotic medication was not signifi- Olanzapine Available since 1996 cantly different from mean BMI SDS Available since 2000 when antipsychotic medication was Risperidone Available since 1994 Available since 1972 started (P =0.84). Available since 1999 Because the groups of subjects with Available since 2004 and without antipsychotic medication Available since 2007 differed significantly regarding age, Available since 2002 sex, and diabetes duration, we used re- Available 1990 until 2010 gression analysis to adjust for these Available since 1997 fl Not available (available in Switzerland) in uencing factors. Available since 2010 Regression Analysis Not available (available in the U.S. since 2009) Our regression modeling adjusted for Available since 2014 (available in the U.S. since 2010) the parameters age, sex, and diabetes duration and used the diabetes center as random effect. First, regression anal- applied to compare rates of severe hypo- received antipsychotic medication. The ysis was implemented to compare sub- glycemia, rates of DKA, and frequency of use of different antipsychotics is de- jects with and without antipsychotic hospital admissions among subjects picted in Table 2. medication (Table 4). BMI SDS was sig- treated with or without typical or atypical Characteristics of the cohorts with nificantly higher (+0.67 vs. +0.50; P = antipsychotics. Hierarchical random ef- and without antipsychotic medications 0.004) and dyslipidemia was more fects regression models (linear, logistic, or Poisson, as appropriate), with the di- abetes center as a random effect and Table 2—Use of antipsychotics* among subjects with type 1 diabetes aged <25 adjusting for age, sex, and diabetes du- years (n =291) ration, were used to assess the covari- Typical antipsychotics Atypical antipsychotics ates BMI SDS, median HbA1c, treatment (n =135) (n =171) strategy, hypertension, dyslipidemia, mi- Pipamperone 29 (10%) Risperidone 122 (42%) croalbuminuria, retinopathy, rate of se- Promethazine 18 (6%) Quetiapine 19 (7%) vere hypoglycemia, and rate of episodes Prochlorperazine 17 (6%) Sulpiride 10 (3%) of DKA. Statistical two-sided significance was assumed at P , 0.05. Haloperidol 16 (6%) Olanzapine 9 (3%) Chlorprothixene 12 (4%) Others 11 (4%) Pimozide 10 (3%) RESULTS Levomepromazine 9 (3%) Cohort Characteristics Others 24 (8%) Of 60,162 subjects with type 1 diabetes *Use of both typical and atypical antipsychotics occurred in 15 subjects (5%). in this prospective survey, 291 (0.48%) 4 Type 1 Diabetes and Antipsychotic Medication Diabetes Care

Table 3—Characteristics of subjects with type 1 diabetes aged <25 years with and adolescents are treated with antipsy- without antipsychotic medication chotics in 2011 (25). In Germany, the Without antipsychotic With antipsychotic observed numbers seem slightly lower: medication medication A recent analysis of data from a German (n = 59,871) (n =291) P health insurance company disclosed Age (years)* 15.5 (11.8, 17.6) 17.0 (14.2, 18.3) ,0.001† that 0.32% of children and adolescents Sex ratio (male/female) 52%/48% 60%/40% 0.006‡ up to the age of 19 years received pre- Immigrant status 13% 19% 0.003‡ scriptions of antipsychotics in 2012 (26). Age at diabetes onset As in our study, risperidone was the drug (years)* 8.9 (5.2,12.2) 8.6 (5.3, 12.2) d prescribed most often in this German Diabetes duration population-based study (26). Moreover, (years)* 5.1 (2.1, 8.7) 7.2 (3.5, 10.9) ,0.001† similar to many studies analyzing trends BMI SDS§ +0.53 (+0.52, +0.54) +0.71 (+0.58, +0.84) 0.003† in prescribing antipsychotic medica- HbA1c (%)* 7.9 (7.1, 9.2) 8.2 (7.3, 9.6) 0.008† tions, more males were treated with (mmol/mol)* 63 (54, 77) 66 (56, 81) antipsychotics in our survey (25,26). In- Insulin dose (IU/kg)* 0.82 (0.64, 1.01) 0.87 (0.68, 1.06) 0.006† terestingly, more subjects with immi- Insulin pump treatment 27% 23% 0.21‡ grant status were included in the group receiving antipsychotic medica- Hypertension 13% 14% 0.46‡ tion compared with the cohort of Dyslipidaemia 30% 37% 0.008‡ patients without antipsychotic medica- Microalbuminuria 33% 37% 0.009‡ tion. This finding is also seen in some Retinopathy 3.5% 4.4% 0.47‡ other studies in the U.S. (3,27). Because Rate of severe we had no data about socioeconomic hypoglycemiak 0.17 (0.002) 0.23 (0.04) 0.008¶ status or education level in our survey, Rate of episodes of DKAk 0.06 (0.001) 0.16 (0.03) ,0.001¶ we were not able to further analyze why more subjects with immigrant status Hospital admissionk 0.51 (0.004) 0.93 (0.07) ,0.001¶ were included in the group receiving an- 2 *Data are expressed as median (lower quartile; upper quartile). †Kruskal-Wallis test. ‡x Test. tipsychotic treatment. §Data are expressed as mean (lower 95% confidence limit; upper 95% confidence limit) kData are expresses as rates per 1 patient-year (confidence interval). ¶Poisson model. Similar to many studies of healthy children, adolescents, and adults, we also found that subjects with type 1 di- frequent (33.6% vs. 28.3%; P =0.045)in antipsychotics and subjects treated abetes and with antipsychotic medica- subjects treated with antipsychotics with atypical antipsychotics were again tion had increased weight (8–13). compared with subjects not taking anti- higher compared with subjects who did Interestingly, our survey showed an in- psychotic medication (Table 4). Glyce- not receive antipsychotic medication creased BMI with both typical and atyp- mic control measured by HbA1c was (33.6% and 34.0% vs. 28.3%); however, ical antipsychotic treatment. Weight not different (P =0.45;Table4).Further- statistical analysis failed to show signif- gain and changes in lipid concentrations more, frequencies of acute diabetes icance (P =0.16andP =0.10;Table4). also have been reported with typical complications, for example, the rates Last, regression analysis revealed that (first-generation) antipsychotics, but of- of severe hypoglycemia and DKA, were subjects treated with typical antipsy- ten to a lesser extent than atypical anti- significantly higher in subjects receiving chotics, but not subjects receiving psychotics (8,9). Moreover, there are antipsychotics (both P , 0.001; Table 4). atypical antipsychotics, had a signifi- marked differences between different Prevalence of hypertension, microalbu- cantly higher rate of severe hypoglyce- antipsychotic agents, both typical and minuria, and retinopathy did not differ mia compared with subjects who did atypical, regarding the amount of weight among subjects with and without anti- not receive antipsychotic medication gain (8,28). For example, medications with psychotic medication. (P , 0.001; Table 4). risperidone (an ) or Second, we used regression analysis to haloperidol (a ) both compare separately treatment with typi- CONCLUSIONS are associated with less weight gain com- cal or atypical antipsychotics (Table 4). To our knowledge, this analysis is the pared with treatment with olanzapine (an Glycemic control, as measured by HbA1c, first to examine metabolic and glycemic atypical agent) or chlorpromazine (a typ- was not different in subjects treated with control in youth with type 1 diabetes ical agent), respectively (8,28,29). Differ- typical antipsychotics compared with sub- treatedwithtypicalandatypicalanti- ent receptor affinities (e.g., 1Haffinity) of jects without antipsychotic medication psychotics. Overall, almost 0.5% of sub- the antipsychotic agents may explain (8.2% vs. 8.4% [66 vs. 68 mmol/mol]; P = jects with type 1 diabetes up to the age some of the different degrees of weight 0.15). By contrast, subjects treated of 25 years were treated with antipsy- gain through, for instance, increased with atypical antipsychotics had signif- chotics in this survey. Population-based appetite (8). Because numerous antipsy- icantly higher HbA1c levels (8.7% vs. data from other European countries, the chotic drugs are used for treatment in 8.4% [72 vs. 68 mmol/mol]; P = 0.022) U.S., and Canada show similar results this survey, we are not able to give any (Table 4). Prevalence of dyslipidemia in (25,26). One survey from Canada re- detailed information about differences both subjects treated with typical ported that 0.64% of children and in BMI as they relate the individual care.diabetesjournals.org Galler and Associates 5

Table 4—Regression analysis adjusting for age, sex, diabetes duration, and with the diabetes center as random effect Without With Medication Medication antipsychotic antipsychotic with typical with atypical Variable Model* medication medication P Model* antipsychotics† P antipsychotics† P

HbA1c, % (mmol/mol) Linear 8.4 (68) 8.4 (68) 0.45 Linear 8.2 vs. 8.4 0.15 8.7 vs. 8.4 0.022‡ (66 vs. 68) (72 vs. 68) BMI SDS Linear +0.50 +0.67 0.004‡ Linear +0.69 vs. +0.50 0.028‡ +0.72 vs. +0.50 0.004‡ Insulin pump treatment Logistic 29.1% 24.5% 0.11 Logistic 29.7 vs. 29.1% 0.90 21.0 vs. 29.1% 0.037‡ Dyslipidemia Logistic 28.3% 33.6% 0.045‡ Logistic 33.6 vs. 28.3% 0.16 34.0 vs. 28.3% 0.10 Hypertension Logistic 11.0% 11.0% 0.99 Logistic 12.0 vs. 11.0% 0.69 9.2 vs. 11.0% 0.42 Microalbuminuria Logistic 23.2% 23.8% 0.79 Logistic 22.4 vs. 23.2% 0.81 25.4 vs. 23.2% 0.49 Retinopathy Logistic 0.8% 0.9% 0.76 Logistic 0.9 vs. 0.9% 0.94 0.9 vs. 0.9% 0.99 Rate of severe hypoglycemia (per 1 patient-year) Poisson 0.19 0.27 ,0.001‡ Poisson 0.34 vs. 0.19 ,0.001‡ 0.22 vs. 0.19 0.29 Rate of episodes of DKA (per 1 patient-year) Poisson 0.05 0.12 ,0.001‡ Poisson 0.13 vs. 0.05 ,0.001‡ 0.12 vs. 0.05 ,0.001‡ Hospital admission (per 1 patient-year) Poisson 0.53 1.06 ,0.001‡ Poisson 0.93 vs. 0.53 ,0.001‡ 1.20 vs. 0.53 ,0.001‡ *Adjusted for age, sex, diabetes duration, and diabetes center. †Versus without antipsychotic medication. ‡Significant at P , 0.05.

antipsychotic agents. Remarkably, in our schizophrenia are known to have a present and, consequently, HbA1c levels survey, BMI SDS among subjects taking poor diet (e.g., a diet richer in fat) remain unchanged. antipsychotic medication was not differ- and often exert less or participate in Furthermore, we examined and com- ent from BMI SDS when antipsychotic inadequate exercise compared with pared the rates of severe hypoglycemia treatment was started. This observation the general population (31). These fac- and DKA, which are important for acute also is consistent with other studies: Sub- tors may also contribute to the re- morbidity and mortality in type 1 diabe- jects with schizophrenia and other psychi- ported changes in lipid metabolism tes. We found significantly higher rates atric disorders are per se more likely to be and serum lipid concentrations. of both DKA and severe hypoglycemia in obese and to have a more unhealthy life- Moreover, we examined glycemic subjects treated with typical antipsy- style (8,30). Unfortunately, there is only a control in subjects treated with antipsy- chotics. Subjects treated with atypical limited number of studies of untreated chotics. Remarkably, glycemic control antipsychotics, who had significantly patients with schizophrenia (8,30). was worse only in subjects treated higher HbA1c levels, had only a higher In addition to the reported difference with atypical antipsychotics, not in sub- rate of DKA, not a higher rate of severe in BMI, we also encountered significant jects treated with typical antipsychotics. hypoglycemia. This association between abnormalities in lipid concentrations in There are several possible explanations more pronounced hyperglycemia, as re- subjects treated with antipsychotics for this finding. Atypical antipsychotic flected by higher HbA1c levels, and a compared with subjects without antipsy- drugs exert direct effects on the b-cells lower rate of severe hypoglycemia is chotic medication. This finding also is in the pancreas, thereby impairing insu- also seen in several other trials and well described in several other studies lin secretion (8). More important, how- may indicate that lower HbA1c levels (31). Again, and similar to the influence ever, recent evidence points toward lead toward an increased risk for severe on weight, different atypical and typical insulin resistance rather than insulin se- hypoglycemia (32,33). Last, we did not antipsychotic drugs seem to be associ- cretion as a cause of hyperglycemia. In- find higher prevalence of diabetes com- ated with a lower or higher risk of hyper- terestingly, in some individuals changes plications such as retinopathy. Because lipidemia (31). Some antipsychotic in insulin resistance occur without in- diabetes duration of the subjects in our agents (e.g., haloperidol) even do not creasesinBMI.Invitrostudieshave survey was less than 10 years, how- seem to influence lipid concentrations shown that some atypical antipsychotic ever, a longer observation time may be significantly (31). To date, why antipsy- drugs inhibit glucose uptake via interac- needed. chotic agents induce dyslipidemia is not tion with glucose transporter proteins Finally, the limitations of our study exactly understood. Weight gain, a well- (e.g., olanzapine) or exert intracellular should be pointed out. The number of described adverse effect of antipsychotic effects (e.g., risperidone). This leads to subjects taking antipsychotic medica- medication, as mentioned above, and insulin resistance, which consequently tion in this survey is relatively small be- obesity lead to hyperlipidemia, and this worsens glycemic control. By contrast, cause schizophrenia and disorders mechanism may play an important role haloperidoldan example of a typical requiring antipsychotic medications are in the pathophysiology of dyslipidemia antipsychoticdhas only marginal ef- rare among the general population as that occurs with antipsychotic medica- fects on glucose transport (8). There- well as among youth with type 1 diabe- tion (31). Furthermore, patients with fore, markedly less insulin resistance is tes (34). Therefore, weak to moderate 6 Type 1 Diabetes and Antipsychotic Medication Diabetes Care

associations could possibly not be dem- medications among children enrolled in Tenn- Stichproben. Monatsschr Kinderheilkd 2001; onstrated because of limited power. Care. Arch Pediatr Adolesc Med 2004;158:753– 149:807–818 Moreover, no sufficient information 759 17. Report of the Second Task Force on Blood 2. Cooper WO, Arbogast PG, Ding H, Hickson Pressure Control in Children–1987. Task Force about the diagnoses for which the anti- GB, Fuchs DC, Ray WA. Trends in prescribing on Blood Pressure Control in Children. National psychotics were prescribed was avail- of antipsychotic medications for US children. Heart, Lung, and Blood Institute, Bethesda, able. Therefore, we are not able to Ambul Pediatr 2006;6:79–83 Maryland. Pediatrics 1987;79:1–25 give any details about the underlying di- 3. Olfson M, Blanco C, Liu L, Moreno C, Laje G. 18. National High Blood Pressure Education agnoses and their possible associations National trends in the outpatient treatment of Program Working Group on Hypertension children and adolescents with antipsychotic Control in Children and Adolescents. Update with metabolic and glycemic control. drugs. Arch Gen Psychiatry 2006;63:679–685 on the 1987 Task Force Report on High Blood Last, because of the cross-sectional re- 4. Olfson M, Blanco C, Liu SM, Wang S, Correll Pressure in Children and Adolescents: a working search design, the results of our analysis CU. National trends in the office-based treat- group report from the National High Blood Pres- are descriptive, and we are not able to ment of children, adolescents, and adults with sure Education Program. Pediatrics 1996;98: – demonstrate any causal effects. antipsychotics. Arch Gen Psychiatry 2012;69: 649 658 1247–1256 19. Wolfsdorf J, Craig ME, Daneman D, et al. In summary, this analysis of a real-life 5. Birnbaum ML, Saito E, Gerhard T, et al. Phar- Diabetic ketoacidosis in children and adoles- survey demonstrated that subjects taking macoepidemiology of antipsychotic use in cents with diabetes. Pediatr Diabetes 2009;10 antipsychotic medication had worse gly- youth with ADHD: trends and clinical implica- (Suppl 12):118–133 cemic control and a higher rate of acute tions. Curr Psychiatry Rep 2013;15:382 20. Gerstl EM, Rabl W, Rosenbauer J, et al. Met- fl complications compared with those not 6. Bobo WV, Cooper WO, Stein CM, et al. Anti- abolic control as re ected by HbA1c in children, psychotics and the risk of type 2 diabetes melli- adolescents and young adults with type-1 dia- taking antipsychotic medication. This ob- tus in children and youth. JAMA Psychiatry betes mellitus: combined longitudinal analysis served adverse metabolic and glycemic 2013;70:1067–1075 including 27,035 patients from 207 centers in control may have a considerate effect 7.CrystalS,OlfsonM,HuangC,PincusH, Germany and Austria during the last decade. on morbidity and long-term prognosis Gerhard T. Broadened use of atypical anti- Eur J Pediatr 2008;167:447–453 in youth with type 1 diabetes taking an- psychotics: safety, effectiveness, and policy 21. Donaghue KC, Chiarelli F, Trotta D, Allgrove challenges. Health Aff (Millwood) 2009;28: J, Dahl-Jorgensen K. Microvascular and macro- tipsychotic medication. Health care w770–w781 vascular complications associated with diabetes teams caring for youth with type 1 diabe- 8. Newcomer JW. Second-generation (atypical) in children and adolescents. Pediatr Diabetes tes on antipsychotic medication need to antipsychotics and metabolic effects: a compre- 2009;10(Suppl 12):195–203 know about these findings. We suggest hensive literature review. CNS Drugs 2005;19 22. Bundesa¨rztekammer (BAK).¨ Kassenarzt-¨ – monitoring metabolic risk factors as well (Suppl. 1):1 93 liche Bundesvereinigung (KBV). Arbeitsgemein- 9. Newcomer JW, Haupt DW. The metabolic ef- schaft der Wissenschaftlichen Medizinischen as providing diabetes education about fects of antipsychotic medications. Can J Psychi- Fachgesellschaften (AWMF). Nationale Versor- the prevention of acute complications. atry 2006;51:480–491 gungsLeitlinie Nierenerkrankungen bei Diabetes 10. Nicol G, Newcomer J. Review: children and im Erwachsenenalter, Langfassung. 1.Auflage. Ver- adolescents with schizophrenia spectrum disor- sion 5. September 2010. Zuletzt geandert:¨ May 2013. Available from http://www.leitlinien.de/ Acknowledgments. We kindly acknowledge ders respond to antipsychotics, but are suscep- the participating diabetes centers in Germany tible to adverse events. Evid Based Ment Health mdb/downloads/nvl/diabetes-mellitus/dm- fl and Austria. The centers are listed in the 2008;11:81 nierenerkrankungen-1au -vers5-lang.pdf. As- Supplementary Data. 11. Hammerman A, Dreiher J, Klang SH, Munitz sessed 12 March 2015 ¨ Funding. Funding was given by the German H, Cohen AD, Goldfracht M. Antipsychotics and 23. Bundesarztekammer. Richtlinie der Bun- Federal Ministry for Education and Research diabetes: an age-related association. Ann Phar- desarztekammer¨ zur Qualitatssicherung¨ labora- – (BMBF) (FKZ 01GI1106), the German Diabetes macother 2008;42:1316 1322 toriumsmedizinischer Untersuchungen. Dtsch – Association, the European Foundation for the 12. Panagiotopoulos C, Ronsley R, Davidson J. Arztebl Int 2008;105:A341 A355 Study of Diabetes (EFSD), and the Dr.-Burger-¨ Increased prevalence of obesity and glucose 24. Sacks DB, Bruns DE, Goldstein DE, Maclaren Busing¨ Foundation. intolerance in youth treated with second- NK, McDonald JM, Parrott M. Guidelines and Duality of Interest. No potential conflicts of generation antipsychotic medications. Can recommendations for laboratory analysis in interest relevant to this article were reported. J Psychiatry 2009;54:743–749 the diagnosis and management of diabetes mel- – Author Contributions. A.G. researched data, 13. Andrade SE, Lo JC, Roblin D, et al. Antipsy- litus. Clin Chem 2002;48:436 472 contributed to the discussion, and wrote, re- chotic medication use among children and risk 25. Ronsley R, Scott D, Warburton WP, et al. A viewed and edited the manuscript. E.B. per- of diabetes mellitus. Pediatrics 2011;128:1135– population-based study of antipsychotic pre- formed the analyses, contributed to discussion, 1141 scription trends in children and adolescents in and reviewed and edited the manuscript. M.M., 14. Maglione M, Maher AR, Hu J, et al. Off-label British Columbia, from 1996 to 2011. Can J Psy- B.B., A.N., H.H., and E.S. researched data, con- use of atypical antipsychotics: an update. Com- chiatry 2013;58:361–369 tributed to discussion, and reviewed the manu- parative effectiveness review no. 43 [report on- 26. Bachmann CJ, Lempp T, Glaeske G, script. R.W.H. researched data, performed the line], September 2011. Rockville, MD, Agency Hoffmann F. Antipsychotic prescription in chil- analyses, contributed to discussion, and reviewed for Healthcare Research and Quality. Available dren and adolescents: an analysis of data from a the manuscript. A.G. is the guarantor of this work from http://effectivehealthcare.ahrq.gov/ehc/ German statutory health insurance company and, as such, takes responsibility for the integrity products/150/786/CER43_Off-LabelAntipsychotics_ from 2005 to 2012. Dtsch Arztebl Int 2014; of the data and the accuracy of the data analysis. execsumm_20110928.pdf. Accessed 6 March 111:25–34 Prior Presentation. The authors presented 2015 27. Olfson M, Blanco C, Wang S, Laje G, Correll preliminary data as an abstract and in poster 15. Kemner C, Willemsen-Swinkels SH, de CU. National trends in the mental health care of form at the European Society for Paediatric Jonge M, Tuynman-Qua H, van Engeland H. children, adolescents, and adults by office-based Endocrinology Annual Meeting, Dublin, Ireland, Open-label study of olanzapine in children physicians. JAMA Psychiatry 2014;71:81–90 18–20 September 2014. with pervasive developmental disorder. J Clin 28. Allison DB, Mentore JL, Heo M, et al. Anti- Psychopharmacol 2002;22:455–460 psychotic-induced weight gain: a comprehen- 16. Kromeyer-Hauschild K, Wabitsch M, Geller sive research synthesis. Am J Psychiatry 1999; References F, et al. Perzentile fur¨ den Body Mass 156:1686–1696 1. Cooper WO, Hickson GB, Fuchs C, Arbogast Index fur¨ das Kindes- und Jugendalter unter 29. Sikich L, Frazier JA, McClellan J, et al. PG, Ray WA. New users of antipsychotic Heranziehung verschiedener deutscher Double-blind comparison of first- and care.diabetesjournals.org Galler and Associates 7

second-generation antipsychotics in early-onset 31. Meyer JM, Koro CE. The effects of antipsy- 33. Rewers A, Chase HP, Mackenzie T, et al. schizophrenia and schizo-affective disorder: chotic therapy on serum lipids: a comprehensive Predictors of acute complications in children findings from the treatment of early-onset review. Schizophr Res 2004;70:1–17 with type 1 diabetes. JAMA 2002;287:2511– schizophrenia spectrum disorders (TEOSS) 32. The Diabetes Control and Complications 2518 study. Am J Psychiatry 2008;165:1420–1431 Trial Research Group. The effect of intensive 34. Butwicka A, Frisen´ L, Almqvist C, Zethelius 30. Stahl SM, Mignon L, Meyer JM. Which treatment of diabetes on the development B, Lichtenstein P. Risks of psychiatric disorders comes first: atypical antipsychotic treatment and progression of long-term complications in and suicide attempts in children and adoles- or cardiometabolic risk? Acta Psychiatr Scand insulin-dependent diabetes mellitus. N Engl J cents with type 1 diabetes: a population-based 2009;119:171–179 Med 1993;329:977–986 cohort study. Diabetes Care 2015;38:453–459