Abstract
Importance Antipsychotics are used increasingly in youth for nonpsychotic and off-label indications, but cardiometabolic adverse effects and (especially) type 2 diabetes mellitus (T2DM) risk have raised additional concern.
Objective To assess T2DM risk associated with antipsychotic treatment in youth.
Data Sources Systematic literature search of PubMed and PsycINFO without language restrictions from database inception until May 4, 2015. Data analyses were performed in July 2015, and additional analyses were added in November 2015.
Study Selection Longitudinal studies reporting on T2DM incidence in youth 2 to 24 years old exposed to antipsychotics for at least 3 months.
Data Extraction and Synthesis Two independent investigators extracted study-level data for a random-effects meta-analysis and meta-regression of T2DM risk.
Main Outcomes and Measures The coprimary outcomes were study-defined T2DM, expressed as cumulative T2DM risk or as T2DM incidence rate per patient-years. Secondary outcomes included the comparison of the coprimary outcomes in antipsychotic-treated youth with psychiatric controls not receiving antipsychotics or with healthy controls.
Results Thirteen studies were included in the meta-analysis, including 185 105 youth exposed to antipsychotics and 310 438 patient-years. The mean (SD) age of patients was 14.1 (2.1) years, and 59.5% were male. The mean (SD) follow-up was 1.7 (2.3) years. Among them, 7 studies included psychiatric controls (1 342 121 patients and 2 071 135 patient-years), and 8 studies included healthy controls (298 803 patients and 463 084 patient-years). Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 (95% CI, 3.45-9.48; P < .001) per 1000 patients. The incidence rate was 3.09 (95% CI, 2.35-3.82; P < .001) cases per 1000 patient-years. Compared with healthy controls, cumulative T2DM risk (odds ratio [OR], 2.58; 95% CI, 1.56-4.24; P < .0001) and incidence rate ratio (IRR) (IRR, 3.02; 95% CI, 1.71-5.35; P < .0001) were significantly greater in antipsychotic-exposed youth. Similarly, compared with psychiatric controls, antipsychotic-exposed youth had significantly higher cumulative T2DM risk (OR, 2.09; 95% CI, 1.50-5 2.90; P < .0001) and IRR (IRR, 1.79; 95% CI, 1.31-2.44; P < .0001). In multivariable meta-regression analyses of 10 studies, greater cumulative T2DM risk was associated with longer follow-up (P < .001), olanzapine prescription (P < .001), and male sex (P = .002) (r2 = 1.00, P < .001). Greater T2DM incidence was associated with second-generation antipsychotic prescription (P ≤ .050) and less autism spectrum disorder diagnosis (P = .048) (r2 = 0.21, P = .044).
Conclusions and Relevance Although T2DM seems rare in antipsychotic-exposed youth, cumulative risk and exposure-adjusted incidences and IRRs were significantly higher than in healthy controls and psychiatric controls. Olanzapine treatment and antipsychotic exposure time were the main modifiable risk factors for T2DM development in antipsychotic-exposed youth. Antipsychotics should be used judiciously and for the shortest necessary duration, and their efficacy and safety should be monitored proactively.
Courtesy of: http://www.medscape.com/viewarticle/857571
"The take-away [message] is that type 2 diabetes is a risk when treating youth with antipsychotics, especially long term, and antipsychotics should therefore be used judiciously and for as short a period as necessary and possible," senior author Christoph U. Correll, MD, of the Hofstra Northwell School of Medicine, Hempstead, New York, told Medscape Medical News....
ReplyDeleteHigher incidence of type 2 diabetes was associated with use of second-generation antipsychotics (P ≤ .050). Interestingly, a lower risk was observed for youth with autism spectrum disorder (P = .048).
The reasons for the lower risk associated with autism are uncertain, the authors noted.
"Whether the lower risk in youth with autism spectrum disorder is driven by other diagnostic groups that are associated with a higher type 2 diabetes risk (eg, mood or psychosis spectrum disorders) or by co-medications used for these patients requires further clarification," the investigators note...(continued)
(continued)"The fact that even compared to psychiatrically ill patients, the cumulative type 2 diabetes risk and the exposure-adjusted risk were still 2.1 times and 1.8 times higher in youth exposed to antipsychotics indicates that antipsychotics play a major role," he said.
ReplyDeleteDr Correll cited a study by his team that was published in 2009. Mentally ill youth who were prescribed antipsychotic drugs experienced dramatic changes in body weight and blood sugar and blood fat parameters within just 3 months of antipsychotic exposure in comparison with mentally ill youth who were prescribed the drugs but who did not take them or who stopped taking them.
The current analysis showed that the number of excess cases of type 2 diabetes in the antipsychotic-exposed group was relatively low ― an excess of 3.11 and 3.57 new type 2 diabetes cases per 1000 psychiatric control patients and healthy persons, respectively. However, the potential consequences remain serious, the authors assert.
"The clinical importance of these findings is underscored by studies showing increased morbidity and mortality associated with an earlier type 2 diabetes onset," the investigators write.
Dr Correll noted that the analysis did not identify drugs that might be associated with a reduced risk for metabolic effects. However, aripiprazole (Abilify, Otsuka Pharmaceutical Co, Ltd) has been cited as being associated with potentially lower risk.
"Other studies suggest indirectly lower type 2 diabetes risk with aripiprazole than with most other antipsychotics, but in young adults, more data are needed," he said...
David Rubin, MD, codirector of PolicyLab at the Children's Hospital of Philadelphia and professor of pediatrics at the Perelman School of Medicine, the University of Pennsylvania, agreed that clinicians need to be more selective in prescribing antipsychotics to the most appropriate patients.
"My major concern is the frequency of use we are seeing for these medications among youth with disruptive behaviors or attention-deficit disorder. I don't believe the evidence supports the use of these medications in many of these cases," Dr Rubin told Medscape Medical News.
"I also worry about how trauma exposure in children can impact the behaviors they display. The answer for this group of youth, and they are many, is not sedation through antipsychotics, it's trauma-focused therapies and the nurturing of stable, attached relationships in their lives."
Dr Rubin, who coauthored research cited in the analysis showing that an increase in the risk for type 2 diabetes in youths who initiated second-generation antibiotics was highest among those who also received antidepressants, agreed that although the incidence of patients developing type 2 diabetes appears relatively small, the risk is still important.
"The authors acknowledge, as we showed in our own study, that the absolute risk for diabetes is low but appears to be real," he said. "That means that clinicians need to weigh that risk against the perceived benefit of using antipsychotics in children.
"At the very least, they should try to minimize the use of these medications to situations that appear to have an evidence base to support their use. They should also try to limit the length of treatment with the antipsychotics, as the longer you treat, the greater the likelihood of harm. Finally, if they are going to treat, they need to be very careful in monitoring for side effects, not just diabetes but other evidence of metabolic dysregulation."
http://www.medscape.com/viewarticle/857571
Bobo WV, Cooper WO, Stein CM, Olfson M, Graham D, Daugherty J, Fuchs DC, Ray WA. Antipsychotics and the risk of type 2 diabetes mellitus in children and youth. JAMA Psychiatry. 2013 Oct;70(10):1067-75.
ReplyDeleteAbstract
IMPORTANCE:
The increased prescribing of antipsychotics for children and youth has heightened concerns that this practice increases the risk of type 2 diabetes mellitus.
OBJECTIVE:
To compare the risk of type 2 diabetes in children and youth 6 to 24 years of age for recent initiators of antipsychotic drugs vs propensity score-matched controls who had recently initiated another psychotropic medication.
DESIGN, SETTING, AND PARTICIPANTS:
Retrospective cohort study of the Tennessee Medicaid program with 28 858 recent initiators of antipsychotic drugs and 14 429 matched controls. The cohort excluded patients who previously received a diagnosis of diabetes, schizophrenia, or some other condition for which antipsychotics are the only generally recognized therapy.
MAIN OUTCOMES AND MEASURES:
Newly diagnosed diabetes during follow-up, as identified from diagnoses and diabetes medication prescriptions.
RESULTS:
Users of antipsychotics had a 3-fold increased risk for type 2 diabetes (HR = 3.03 [95% CI = 1.73-5.32]), which was apparent within the first year of follow-up (HR = 2.49 [95% CI = 1.27-4.88]). The risk increased with cumulative dose during follow-up, with HRs of 2.13 (95% CI = 1.06-4.27), 3.42 (95% CI = 1.88-6.24), and 5.43 (95% CI = 2.34-12.61) for respective cumulative doses (gram equivalents of chlorpromazine) of more than 5 g, 5 to 99 g, and 100 g or more (P < .04). The risk remained elevated for up to 1 year following discontinuation of antipsychotic use (HR = 2.57 [95% CI = 1.34-4.91]). When the cohort was restricted to children 6 to 17 years of age, antipsychotic users had more than a 3-fold increased risk of type 2 diabetes (HR = 3.14 [95% CI = 1.50-6.56]), and the risk increased significantly with increasing cumulative dose (P < .03). The risk was increased for use restricted to atypical antipsychotics (HR = 2.89 [95% CI = 1.64-5.10]) or to risperidone (HR = 2.20 [95% CI = 1.14-4.26]).
CONCLUSIONS AND RELEVANCE:
Children and youth prescribed antipsychotics had an increased risk of type 2 diabetes that increased with cumulative dose.
Courtesy of: http://www.medscape.com/viewarticle/809942
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 Oct 28;302(16):1765-73.
ReplyDeleteAbstract
CONTEXT:
Cardiometabolic effects of second-generation antipsychotic medications are concerning but have not been sufficiently studied in pediatric and adolescent patients naive to antipsychotic medication.
OBJECTIVE:
To study the association of second-generation antipsychotic medications with body composition and metabolic parameters in patients without prior antipsychotic medication exposure.
DESIGN, SETTING, AND PATIENTS:
Nonrandomized Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) cohort study, conducted between December 2001 and September 2007 at semi-urban, tertiary care, academic inpatient and outpatient clinics in Queens, New York, with a catchment area of 4.5-million individuals. Of 505 youth aged 4 to 19 years with 1 week or less of antipsychotic medication exposure, 338 were enrolled (66.9%). Of these patients, 272 had at least 1 postbaseline assessment (80.5%), and 205 patients [corrected] completed the study (60.7%). Patients had mood spectrum (n = 130; 47.8%), schizophrenia spectrum (n = 82; 30.1%), and disruptive or aggressive behavior spectrum (n = 60; 22.1%) disorders. Fifteen patients who refused participation or were nonadherent served as a comparison group.
INTERVENTION:
Treatment with aripiprazole, olanzapine, quetiapine, or risperidone for 12 weeks.
MAIN OUTCOME MEASURES:
Weight gain and changes in lipid and metabolic parameters.
RESULTS:
After a median of 10.8 weeks (interquartile range, 10.5-11.2 weeks) of treatment, weight increased by 8.5 kg (95% confidence interval [CI], 7.4 to 9.7 kg) with olanzapine (n = 45), by 6.1 kg (95% CI, 4.9 to 7.2 kg) with quetiapine (n = 36), by 5.3 kg (95% CI, 4.8 to 5.9 kg) with risperidone (n = 135), and by 4.4 kg (95% CI, 3.7 to 5.2 kg) with aripiprazole (n = 41) compared with the minimal weight change of 0.2 kg (95% CI, -1.0 to 1.4 kg) in the untreated comparison group (n = 15). With olanzapine and quetiapine, respectively, mean levels increased significantly for total cholesterol (15.6 mg/dL [95% CI, 6.9 to 24.3 mg/dL] P < .001 and 9.1 mg/dL [95% CI, 0.4 to 17.7 mg/dL] P = .046), triglycerides (24.3 mg/dL [95% CI, 9.8 to 38.9 mg/dL] P = .002 and 37.0 mg/dL [95% CI, 10.1 to 63.8 mg/dL] P = .01), non-high-density lipoprotein (HDL) cholesterol (16.8 mg/dL [95% CI, 9.3 to 24.3 mg/dL] P < .001 and 9.9 mg/dL [95% CI, 1.4 to 18.4 mg/dL] P = .03), and ratio of triglycerides to HDL cholesterol (0.6 [95% CI, 0.2 to 0.9] P = .002 and (1.2 [95% CI, 0.4 to 2.0] P = .004). With risperidone, triglycerides increased significantly (mean level, 9.7 mg/dL [95% CI, 0.5 to 19.0 mg/dL]; P = .04). Metabolic baseline-to-end-point changes were not significant with aripiprazole or in the untreated comparison group.
CONCLUSIONS:
First-time second-generation antipsychotic medication use was associated with significant weight gain with each medication. Metabolic changes varied among the 4 antipsychotic medications.
Erratum in JAMA. 2009 Dec 2;302(21):2322.
Anagnostou E, Aman MG, Handen BL, Sanders KB, Shui A, Hollway JA, Brian J, Arnold LE, Capano L, Hellings JA, Butter E, Mankad D, Tumuluru R, Kettel J, Newsom CR, Hadjiyannakis S, Peleg N, Odrobina D, McAuliffe-Bellin S, Zakroysky P, Marler S, Wagner A, Wong T, Macklin EA, Veenstra-VanderWeele J. Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2016 Aug 24. doi:10.1001/jamapsychiatry.2016.1232. [Epub ahead of print]
ReplyDeleteAbstract
IMPORTANCE:
Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use.
OBJECTIVE:
To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years.
DESIGN, SETTING, AND PARTICIPANTS:
A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015.
INTERVENTIONS:
Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.
MAIN OUTCOMES AND MEASURES:
The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.
RESULTS:
Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).
CONCLUSIONS AND RELEVANCE:
Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.
Courtesy of: https://neurologistconnect.com/newsdetail/57c14882634e8873198b4567?SKUID6656d46c04553656b04bf4a8e0248071&mkt_tok=eyJpIjoiT0RBd016Y3laRE0yWkdOaiIsInQiOiJLeWZrUjJtTWt0NjRwbElwSXpJWTRQTVh5eHNIaFF1WmNDT2ZJXC9ERzV3M1hXa2hTMWxmNmNxWmZSN3NIWmRmbnhyaUZzXC8yUUNUVml2V1RKRG83T0ZvRFNqQm1mMklDb0lpN0RKT01KWm9vPSJ9