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Original article
peer-reviewed

Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations



Abstract

In recent years, antipsychotic medications have increasingly been used in pediatric and geriatric populations, despite the fact that many of these drugs were approved based on clinical trials in adult patients only. Preliminary studies have shown that the “off-label” use of these drugs in pediatric and geriatric populations may result in adverse events not found in adults. In this study, we utilized the large-scale U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) database to look at differences in adverse events from antipsychotics among adult, pediatric, and geriatric populations. We performed a systematic analysis of the FDA AERS database using MySQL by standardizing the database using structured terminologies and ontologies. We compared adverse event profiles of atypical versus typical antipsychotic medications among adult (18-65), pediatric (age < 18), and geriatric (> 65) populations. We found statistically significant differences between the number of adverse events in the pediatric versus adult populations with aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene, and between the geriatric versus adult populations with aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone (p < 0.05, with adjustment for multiple comparisons). Furthermore, the particular types of adverse events reported also varied significantly between each population for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (Chi-square, p < 10-6). Diabetes was the most commonly reported side effect in the adult population, compared to behavioral problems in the pediatric population and neurologic symptoms in the geriatric population. We also found discrepancies between the frequencies of reports in AERS and in the literature. Our analysis of the FDA AERS database shows that there are significant differences in both the numbers and types of adverse events among these age groups and between atypical and typical antipsychotics. It is important for clinicians to be mindful of these differences when prescribing antipsychotics, especially when prescribing medications off-label.

Introduction

While antipsychotic medications were initially approved based on clinical trials in adult populations, they are commonly prescribed “off-label” in pediatric and geriatric populations [1-2]. In addition, they are increasingly being prescribed to children. Between the 1993 - 1998 and 2005 - 2009 time periods, visits including a prescription for antipsychotics per 100 people increased from 0.24 to 1.83 for children, 0.78 to 3.76 for adolescents, and 3.25 to 6.18 for adults; moreover, antipsychotics were included in 31.1% of youth visits to psychiatrists [3]. While antipsychotics are among the most effective drugs for the treatment of schizophrenia, mania, or acute psychotic reactions, these medications are often prescribed to children and adolescents for non-FDA approved indications, such as disruptive behaviors and aggression [4-5]. Similarly, antipsychotics are frequently used in the elderly and are prescribed to more than a quarter of Medicare patients in nursing homes, with common conditions including dementia, delirium, and behavioral disturbances [2]. However, the use of these medications may result in unanticipated adverse events that are specific to the pediatric and geriatric populations [6]. In our study, we sought to elucidate the differences in adverse events between pediatric, adult, and geriatric populations using the FDA’s Adverse Events Reporting System (AERS), a database that has collected information about adverse events since 1998 [7]. AERS is the FDA’s primary tool for post-marketing adverse event surveillance, with over 250,000 adverse event reports annually [8]. A key strength of the AERS database is the ability to analyze a massive dataset and discover potentially new information regarding drug-related adverse events warranting further investigation. For instance, a recent paper probed the AERS database and found a potential link between amisulpride, cyamemazine, and olanzapine and torsadogenic risk [9]. Drug manufacturers are required to submit adverse event reports, while healthcare providers can voluntarily submit information.

Materials & Methods

We initially imported AERS quarterly data from January 2004 to September 2008 into the MySQL program (v.1.2.17) (Oracle Corp., Redwood Shores, CA). A table was created that mapped all the various drug names for antipsychotics to a generic name and a drug class (typical vs. atypical) using RxNorm (U.S. National Library of Medicine, Bethesda, MD) and Micromedex® (Truven Health Analytics, Greenwood Village, CO) (Table 1). Next, we joined this table with the AERS drug table (matching by DRUGNAME), the AERS demo table (matching by ISR, which stands for individual safety report), and the AERS REAC table (also matching by ISR). We first retrieved the total number of adverse events associated with each drug name, generic name, and drug class. Next, we created a yearage variable (which standardized all ages in AERS to be reported in years using the AGE and AGE_COD variables) as well as the GNDR_COD variable (which was reported as either “M” or “F”) in order to repeat this analysis on the following five subgroups: yearage < 18 (pediatrics), 18 ≥ yearage ≤ 65 (adults), and yearage > 65 (geriatrics), GNDR_COD = “M” (males), and GNDR_COD = ”F” (females).

Drug Name Generic Name Drug Class
Abilify Aripiprazole Atypicals
Aripiprazole Aripiprazole Atypicals
Chlorpromazine Chlorpromazine Typicals
Clozapine Clozapine Atypicals
Clozaril Clozapine Atypicals
Decazate Fluphenazine Typicals
Dozine Chlorpromazine Typicals
Fazalco Clozapine Atypicals
Fentazin Perphenazine   Typicals
Fluphenazine Fluphenazine Typicals
Fortunan Haloperidol Typicals
Geodon Ziprasidone Atypicals
Haldol Haloperidol Typicals
Haloperidol Haloperidol Typicals
Invega Paliperidone Atypicals
Kentace Haloperidol Typicals
Largactil Chlorpromazine Typicals
Loxapac Loxapine Typicals
Loxapine Loxapine Typicals
Loxitane Loxapine Typicals
Mellaril Thioridazine Typicals
Mesoridazine Mesoridazine Typicals
Moban Molindone Typicals
Moditen Fluphenazine Typicals
Navane Thiothixene Typicals
Noxene Thiothixene Typicals
Olanzapine Olanzapine Atypicals
Orap Pimozide Typicals
Ormazine Chlorpromazine Typicals
Permitil Fluphenazine Typicals
Perphenazine Perphenazine Typicals
Pimozide Pimozide Typicals
Primazine Promazine Typicals
Prolixin Fluphenazine Typicals
Promazine Promazine Typicals
Quetiapine Quetiapine Atypicals
Rideril Thioridazine Typicals
Risperdal Risperidone Atypicals
Risperidone Risperidone Atypicals
Serenace Haloperidol Typicals
Serentil Mesoridazine Typicals
Seroquel Quetiapine Atypicals
Sparine Promazine Typicals
Stelazine Trifluoperazine Typicals
Symbyax Olanzapine Atypicals
Thioridazine Thioridazine Typicals
Thiothixene Thiothixene Typicals
Thorazine Chlorpromazine Typicals
Trifluoperazine Trifluoperazine Typicals
Trilafon Promazine Typicals
Vesprin Triflupromazine Typicals
Ziprasidone Ziprasidone Atypicals
Zyprexa Olanzapine Atypicals

Next, for each drug, we computed the percent of antipsychotic-related adverse events that the drug represented in each population. We then used the z-test of proportions to compare this percent for each drug in the following categories: pediatrics vs. adults, adults vs. geriatrics, and males vs. females. This process was conducted separately for typical and atypical drugs. This resulted in a z-score and a p-value for each comparison, which was then adjusted using a Bonferroni correction for multiple comparisons, making the significance threshold 0.05/26 = 1.92 x 10-3.

Afterward, we retrieved the count of each individual adverse event associated with each generic drug, ordered by the frequency of occurrence in each population. We made sure not to include irrelevant or vague side effects in our top results, excluding terms such as “DRUG INTERACTION,” “ACCIDENTAL EXPOSURE,” and “ACCIDENTAL DRUG INTAKE BY CHILD.” In order to compare the frequencies of the different adverse events in the adult, pediatric, and geriatric populations, we conducted a Chi-square test. For each drug, we selected the top five adverse events in adults and added a sixth column that contained the sum of all other adverse events. We chose the top five since this minimized the number of cells in the Chi-square calculation that contained an expected value less than 5, which is not ideal for the Chi-square test. Next, we compared the frequency of these particular adverse events in the adult, pediatric, and geriatric populations using a 3 by 6 Chi-square table with 10 degrees of freedom, and we calculated p-values for each of seven major drugs—aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone—using the R statistical program (v2.12.2). We also used the MedRDA (Medical Directory for Regulatory Activities: International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland) hierarchy to map MedDRA Preferred Terms (the default FDA coding) to high-level terms and determined the frequency of the high-level terms in the three populations.

Next, we took the list of the top five adverse events for the seven drugs in the three populations and used Medical Subject Headings (MeSH terms) to evaluate how many times a particular drug-adverse event combination was indexed in PubMed for the three populations. For instance, for the side-effect “TREMOR” for aripiprazole in the geriatric population, we would have used the following search term: "aripiprazole"[Substance Name] AND ("Aged"[Mesh]) AND tremor. We then compared the number of reports in AERS and in the literature. For the drug, population, and adverse event combinations that had fewer than five reports in the literature, we manually examined the results to ensure their validity and highlighted the ones that we confirmed to have less than five reports.

Results

A summary of the populations we studied is shown in Table 2.

Category Value
Total number of patients 61,380
Mean age ± SD 45.7 ± 20.0
Patients where age < 18 3,578
Patients where age ≥ 18 and age 65 32,660
Patients where age > 65 7,260
Patients where age is not available 17,882
Male patients 27,783
Female patients 29,780
Gender NA (null, unknown, or not specified) 3,817

The percentage of antipsychotic-related side effects was often significantly different in the pediatric, adult, and geriatric populations for atypical and typical antipsychotics as shown in Tables 3-4.

Generic Name % of Adverse Events p-value (vs. Adults) Statistical Significance
Pediatrics Adults Geriatrics Pediatrics Geriatrics
Aripiprazole 25.9 9.8 4.8 0 0 Both
Clozapine 4.6 17.3 13.9 0 2.7e-14 Both
Olanzapine 16.1 26.0 25.6 0 0.23 Pediatrics
Paliperidone 0.6 0.6 0.2 0.43 3.5e-5 Geriatrics
Quetiapine 24.4 27.2 26.1 2.6e-5 0.019 Pediatrics
Risperidone 23.3 14.4 27.5 0 0 Both
Ziprasidone 5.1 4.6 1.9 0.077 0 Geriatrics
TOTALS 100.0 100.0 100.0  

Generic Name % of Adverse Events p-value (vs. Adults) Statistical Significance
Pediatrics Adults Geriatrics Pediatrics Geriatrics
Chlorpromazine 20.3 17.1 12.1 0.066 3.31e-6 Geriatrics
Fluphenazine 0.3 5.1 2.4 4.3e-5 4.39e-6 Both
Haloperidol 64.9 56.3 72.8 0.0011 0 Both
Loxapine 2.8 2.7 1.9 0.46 0.043 --
Mesoridazine 0.0 0.2 0.1 0.20 0.27 --
Molindone 0.9 0.3 0.6 0.017 0.018 --
Perphenazine 0.3 2.7 2.3 0.0038 0.19 --
Pimozide 3.4 1.6 1.3 0.0082 0.17 --
Promazine 0.6 2.8 0.1 0.0095 9.39e-10 Geriatrics
Thioridazine 5.5 3.9 3.4 0.070 0.20 --
Thiothixene 0.0 4.5 0.9 4.9e-5 1.24e-10 Both
Trifluoperazine 0.9 2.9 2.0 0.017 0.031 --
TOTALS 100.0 100.0 100.0  

Eight antipsychotics were associated with a significant difference in the number of adverse events in the pediatric vs. adult populations, including aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene. Ten antipsychotics were associated with a significant difference in the number of adverse events in the adult vs. geriatric populations, including aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone. When we compared the distributions of adverse events in the adult population to the pediatric and geriatric populations, Chi-square tests revealed that they were significantly different, as the p-values were 4.33e-32, 1.68e-92, 2.60e-35, 6.96e-106, 4.50e-124, 3.43e-65, and 1.35e-7, respectively, for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone. Tables comparing the number of reports in the literature to those in the AERS database for the top five adverse events in seven major antipsychotics revealed some outliers in the three populations, as evidenced by the reports with less than five cases in the literature (Tables 5-6).

Generic Name Event Pediatrics N Pediatrics
Aripiprazole WEIGHT INCREASED 102
Aripiprazole TREMOR 86
Aripiprazole DYSTONIA 82
Aripiprazole SOMNOLENCE 63
Aripiprazole EXTRAPYRAMIDAL DISORDER 62
Aripiprazole OTHERS 3,087
Clozapine TACHYCARDIA 37
Clozapine GRANULOCYTOPENIA 32
Clozapine SOMNOLENCE 31
Clozapine WHITE BLOOD CELL COUNT DECREASED 26
Clozapine SEDATION 21
Clozapine OTHERS 1,069
Haloperidol SOMNOLENCE 35
Haloperidol TREMOR 23
Haloperidol EXTRAPYRAMIDAL DISORDER 18
Haloperidol MUSCLE SPASMS 15
Haloperidol NEUROLEPTIC MALIGNANT SYNDROME 14
Haloperidol OTHERS 770
Olanzapine WEIGHT INCREASED 106
Olanzapine AGGRESSION 69
Olanzapine SUICIDAL IDEATION 58
Olanzapine ABNORMAL BEHAVIOUR 46
Olanzapine COMPLETED SUICIDE 44
Olanzapine OTHERS 3,755
Quetiapine WEIGHT INCREASED 121
Quetiapine SUICIDAL IDEATION 80
Quetiapine TACHYCARDIA 74
Quetiapine CONVULSION 72
Quetiapine AGGRESSION 70
Quetiapine OTHERS 4,745
Risperidone AGGRESSION 112
Risperidone WEIGHT INCREASED 69
Risperidone CONVULSION 66
Risperidone SUICIDAL IDEATION 65
Risperidone ABNORMAL BEHAVIOUR 54
Risperidone OTHERS 4,015
Ziprasidone DYSTONIA 26
Ziprasidone SUICIDAL IDEATION 25
Ziprasidone DEPRESSION 20
Ziprasidone SUICIDE ATTEMPT 20
Ziprasidone WEIGHT INCREASED 19
Ziprasidone OTHERS 943

Generic Name Event Geriatrics N Geriatrics
Aripiprazole TREMOR 27
Aripiprazole NEUROLEPTIC MALIGNANT SYNDROME 22
Aripiprazole PARKINSONISM 21
Aripiprazole DEATH 18
Aripiprazole GAIT DISTURBANCE 15
Aripiprazole OTHERS 1,087
Clozapine DEATH 174
Clozapine PNEUMONIA 100
Clozapine PYREXIA 63
Clozapine SOMNOLENCE 50
Clozapine FALL 46
Clozapine OTHERS 3,117
Haloperidol AGITATION 78
Haloperidol CONFUSIONAL STATE 75
Haloperidol FALL 68
Haloperidol PYREXIA 67
Haloperidol DELIRIUM 62
Haloperidol OTHERS 5,196
Olanzapine FALL 175
Olanzapine CONFUSIONAL STATE 142
Olanzapine DIABETES MELLITUS 138
Olanzapine CEREBROVASCULAR ACCIDENT 107
Olanzapine PNEUMONIA 100
Olanzapine OTHERS 9,494
Quetiapine FALL 155
Quetiapine DEATH 111
Quetiapine CONFUSIONAL STATE 107
Quetiapine AGITATION 103
Quetiapine PNEUMONIA 91
Quetiapine OTHERS 7,377
Risperidone SOMNOLENCE 161
Risperidone DEATH 159
Risperidone CONFUSIONAL STATE 152
Risperidone FALL 135
Risperidone ASTHENIA 117
Risperidone OTHERS 8,770
Ziprasidone MYOCARDIAL INFARCTION 15
Ziprasidone COMA 15
Ziprasidone LOSS OF CONSCIOUSNESS 11
Ziprasidone SEDATION 11
Ziprasidone AGITATION 11
Ziprasidone OTHERS 706

Chi-square analysis was performed to compare the actual distribution of adverse events between the different populations for each drug. Seven commonly prescribed antipsychotics are presented in Table 7: aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone.

Generic Name Event Adults N Peds N Adults N Geriatrics p-Value
Aripiprazole DIABETES MELLITUS 11 288 10  
Aripiprazole WEIGHT INCREASED 102 235 13  
Aripiprazole INSOMNIA 11 227 12  
Aripiprazole TREMOR 86 177 27  
Aripiprazole ANXIETY 13 158 4  
Aripiprazole OTHERS 3,259 14,491 1,124 4.3e-32
Clozapine GRANULOCYTOPENIA 32 611 27  
Clozapine LEUKOPENIA 11 390 20  
Clozapine PYREXIA 16 376 63  
Clozapine DEATH 0 342 174  
Clozapine TACHYCARDIA 37 309 17  
Clozapine OTHERS 1,120 29,669 3,249 1.7e-92
Haloperidol DIABETES MELLITUS 0 205 8  
Haloperidol NEUROLEPTIC MALIGNANT SYNDROME 14 196 44  
Haloperidol SOMNOLENCE 35 148 41  
Haloperidol PYREXIA 10 147 67  
Haloperidol HYPERTENSION 2 128 12  
Haloperidol OTHERS 814 14,528 5,374 2.6e-35
Olanzapine DIABETES MELLITUS 42 2,197 138  
Olanzapine WEIGHT INCREASED 106 1,464 64  
Olanzapine HYPERTENSION 21 906 56  
Olanzapine PANCREATITIS 27 865 43  
Olanzapine DIABETES MELLITUS NON-INSULIN-DEPENDENT 6 720 21  
Olanzapine OTHERS 3,876 62,460 9,834 7.0e-106
Quetiapine DIABETES MELLITUS 39 2,066 55  
Quetiapine PANCREATITIS 16 871 28  
Quetiapine WEIGHT INCREASED 121 662 18  
Quetiapine SOMNOLENCE 70 528 79  
Quetiapine DIZZINESS 41 473 75  
Quetiapine OTHERS 4,875 48,314 7,689 4.5e-124
Risperidone DIABETES MELLITUS 20 614 34  
Risperidone WEIGHT INCREASED 69 390 15  
Risperidone DEPRESSION 46 327 41  
Risperidone SOMNOLENCE 47 292 161  
Risperidone NEUROLEPTIC MALIGNANT SYNDROME 19 262 37  
Risperidone OTHERS 4,180 32,300 9,206 3.4e-65
Ziprasidone DIABETES MELLITUS 4 243 3  
Ziprasidone WEIGHT INCREASED 19 173 2  
Ziprasidone ANXIETY 15 116 5  
Ziprasidone DEPRESSION 20 105 3  
Ziprasidone INSOMNIA 12 104 6  
Ziprasidone OTHERS 983 10,316 750 1.3e-7

The top five adverse events for less common drugs are listed in Table 8.

Generic Name Event Pediatrics N Event Adults N Event Geriatrics N
Chlorpromazine DRUG EXPOSURE DURING PREGNANCY 12 DIABETES MELLITUS 100 WEIGHT DECREASED 17
Chlorpromazine SOMNOLENCE 9 VOMITING 59 DIARRHOEA 16
Chlorpromazine AGGRESSION 7 NEUROLEPTIC MALIGNANT SYNDROME 52 DEHYDRATION 15
Chlorpromazine DRUG INEFFECTIVE 6 CONVULSION 51 PNEUMONIA 14
Chlorpromazine WEIGHT INCREASED 6 PYREXIA 50 SEPSIS 13
Fluphenazine ARRHYTHMIA 1 DIABETES MELLITUS 26 CONFUSIONAL STATE 6
Fluphenazine MYOCARDITIS 1 HYPERTENSION 22 URINARY TRACT INFECTION 5
Fluphenazine PYREXIA 1 WEIGHT INCREASED 17 SOMNOLENCE 5
Fluphenazine NA 0 HYPONATRAEMIA 17 SEDATION 5
Fluphenazine NA 0 HYPOTENSION 16 TACHYCARDIA 3
Loxapine PROTHROMBIN LEVEL DECREASED 3 PYREXIA 15 DYSPHAGIA 5
Loxapine CONGENITAL GENITOURINARY ABNORMALITY 2 SEPSIS 11 CONFUSIONAL STATE 4
Loxapine CRYPTORCHISM 2 AGITATION 10 DEPRESSED LEVEL OF CONSCIOUSNESS 4
Loxapine DRUG EXPOSURE DURING PREGNANCY 2 LACTIC ACIDOSIS 10 SOMNOLENCE 3
Loxapine RENAL CYST 2 BLOOD CREATINE PHOSPHOKINASE INCREASED 9 ANAEMIA 3
Mesoridazine NA 0 AGGRESSION 4 MALAISE 1
Mesoridazine NA 0 EXCESSIVE MASTURBATION 3 STOMATITIS 1
Mesoridazine NA 0 RASH PAPULAR 3 TARDIVE DYSKINESIA 1
Mesoridazine NA 0 SKIN ULCER 3 NA 0
Mesoridazine NA 0 RASH 2 NA 0
Molindone NEUROLEPTIC MALIGNANT SYNDROME 2 PRESCRIBED OVERDOSE 3 HAEMOGLOBIN DECREASED 3
Molindone MYOSITIS 1 CONVULSION 3 MYELOID LEUKAEMIA 3
Molindone PYREXIA 1 DIABETES MELLITUS NON-INSULIN-DEPENDENT 2 PLATELET COUNT DECREASED 3
Molindone VIRAL MYOSITIS 1 ANGER 2 WHITE BLOOD CELL COUNT INCREASED 3
Molindone RASH 1 ABDOMINAL DISTENSION 2 TARDIVE DYSKINESIA 3
Paliperidone NEUROLEPTIC MALIGNANT SYNDROME 10 GALACTORRHOEA 30 DYSPNOEA 4
Paliperidone HEADACHE 9 EXTRAPYRAMIDAL DISORDER 23 DEEP VEIN THROMBOSIS 3
Paliperidone CONFUSIONAL STATE 8 AKATHISIA 17 TREMOR 3
Paliperidone PALPITATIONS 8 OEDEMA PERIPHERAL 17 RENAL FAILURE 3
Paliperidone DYSTONIA 6 DYSTONIA 12 CONFUSIONAL STATE 2
Perphenazine NA 0 VOMITING 11 DRUG INEFFECTIVE 6
Perphenazine NA 0 COMPLETED SUICIDE 10 HYPOTENSION 5
Perphenazine NA 0 DIABETES MELLITUS 10 INSOMNIA 4
Perphenazine NA 0 DRUG INTERACTION 8 CEREBRAL INFARCTION 4
Perphenazine NA 0 DRUG INEFFECTIVE 8 AGRANULOCYTOSIS 3
Pimozide WEIGHT INCREASED 4 CARDIAC ARREST 12 COMA 4
Pimozide DIARRHOEA 4 SUICIDE ATTEMPT 8 MEDICATION ERROR 4
Pimozide RECTAL HAEMORRHAGE 4 DRUG INTERACTION 7 TOXIC SKIN ERUPTION 3
Pimozide SOMNOLENCE 3 OVERDOSE 6 THROMBOCYTOPENIA 3
Pimozide ANOREXIA 2 ANXIETY 6 FALL 2
Promazine NEONATAL DIABETES MELLITUS 1 DIABETES MELLITUS 33 DRUG INTERACTION 2
Promazine PREMATURE BABY 1 PANCREATITIS 15 METHYLMALONIC ACIDURIA 1
Promazine DEATH 1 MYOCARDIAL INFARCTION 15 MUSCLE RIGIDITY 1
Promazine DIAPHRAGMATIC HERNIA 1 BLOOD PRESSURE DECREASED 14 CONFUSIONAL STATE 1
Promazine PULMONARY HYPOPLASIA 1 MYOCARDITIS 14 PLATELET COUNT INCREASED 1
Thioridazine NAUSEA 8 HEADACHE 32 CONFUSIONAL STATE 9
Thioridazine ANOREXIA 8 DIZZINESS 29 HYPERGLYCAEMIA 8
Thioridazine VOMITING 5 DEPRESSION 25 ANXIETY 7
Thioridazine ACHOLIA 5 ANXIETY 24 BACK PAIN 7
Thioridazine AGGRESSION 5 WEIGHT DECREASED 22 DEPRESSION 6
Thiothixene NA 0 DIABETES MELLITUS 63 DYSPNOEA 4
Thiothixene NA 0 WEIGHT INCREASED 56 CEREBROVASCULAR ACCIDENT 3
Thiothixene NA 0 HEADACHE 33 NAUSEA 3
Thiothixene NA 0 PANCREATITIS 33 TARDIVE DYSKINESIA 3
Thiothixene NA 0 CHEST PAIN 31 ANTICHOLINERGIC SYNDROME 2
Trifluoperazine SEXUAL OFFENCE 1 DIABETES MELLITUS 32 CEREBROVASCULAR ACCIDENT 6
Trifluoperazine CONVULSION 1 INSOMNIA 16 CEREBRAL ATROPHY 5
Trifluoperazine DEPRESSION 1 DEPRESSION 13 TRANSIENT ISCHAEMIC ATTACK 5
Trifluoperazine INJURY 1 DIABETIC KETOACIDOSIS 12 TREMOR 5
Trifluoperazine MEDICATION ERROR 1 PANCREATITIS 12 MYOCARDIAL INFARCTION 4

The top five adverse events for the seven major antipsychotics mapped to MedDRA high-level terms are listed in Table 9.

Generic Event Pediatrics N Event Adults N Event Geriatrics N
Aripiprazole Neurological signs and symptoms NEC 196 Neurological signs and symptoms NEC 577 Neurological signs and symptoms NEC 56
Aripiprazole Dyskinesias and movement disorders NEC 172 Dyskinesias and movement disorders NEC 445 General signs and symptoms NEC 36
Aripiprazole Disturbances in consciousness NEC 143 Anxiety symptoms 420 Muscle tone abnormal 33
Aripiprazole Physical examination procedures 133 General signs and symptoms NEC 408 Dyskinesias and movement disorders NEC 33
Aripiprazole General signs and symptoms NEC 117 Physical examination procedures 402 Parkinson's disease and parkinsonism 29
Clozapine Disturbances in consciousness NEC 78 White blood cell analyses 1,222 General signs and symptoms NEC 193
Clozapine White blood cell analyses 56 Neutropenias 1,137 Death and sudden death 192
Clozapine Neutropenias 52 Disturbances in consciousness NEC 952 Disturbances in consciousness NEC 145
Clozapine Rate and rhythm disorders NEC 42 General signs and symptoms NEC 887 Lower respiratory tract and lung infections 121
Clozapine Neurological signs and symptoms NEC 39 Neurological signs and symptoms NEC 831 Lower respiratory tract infections NEC 117
Haloperidol Disturbances in consciousness NEC 51 Disturbances in consciousness NEC 471 Neurological signs and symptoms NEC 246
Haloperidol Medication errors due to accidental exposures 50 Neurological signs and symptoms NEC 425 Disturbances in consciousness NEC 162
Haloperidol Muscle tone abnormal 39 General signs and symptoms NEC 381 General signs and symptoms NEC 141
Haloperidol Dyssomnias 35 Breathing abnormalities 278 Ventricular arrhythmias and cardiac arrest 140
Haloperidol Dyskinesias and movement disorders NEC 33 Liver function analyses 274 Anxiety symptoms 126
Olanzapine Suicidal and self-injurious behavior 198 Diabetes mellitus (incl subtypes) 2,403 Disturbances in consciousness NEC 374
Olanzapine Physical examination procedures 150 Physical examination procedures 2,016 Neurological signs and symptoms NEC 355
Olanzapine Neurological signs and symptoms NEC 134 General signs and symptoms NEC 1,556 General signs and symptoms NEC 303
Olanzapine Behavior and socialization disturbances 130 Disturbances in consciousness NEC 1,551 Non-site specific injuries NEC 201
Olanzapine General signs and symptoms NEC 126 Neurological signs and symptoms NEC 1,312 Liver function analyses 182
Quetiapine Suicidal and self-injurious behavior 235 Diabetes mellitus (incl subtypes) 2,432 Neurological signs and symptoms NEC 331
Quetiapine Neurological signs and symptoms NEC 205 General signs and symptoms NEC 1,531 Disturbances in consciousness NEC 292
Quetiapine Physical examination procedures 178 Neurological signs and symptoms NEC 1,514 General signs and symptoms NEC 221
Quetiapine General signs and symptoms NEC 172 Disturbances in consciousness NEC 1,386 Non-site specific injuries NEC 181
Quetiapine Disturbances in consciousness NEC 170 Suicidal and self-injurious behavior 1,120 Circulatory collapse and shock 170
Risperidone Behavior and socialization disturbances 217 General signs and symptoms NEC 966 Disturbances in consciousness NEC 441
Risperidone Suicidal and self-injurious behavior 202 Disturbances in consciousness NEC 870 Neurological signs and symptoms NEC 351
Risperidone Neurological signs and symptoms NEC 194 Neurological signs and symptoms NEC 867 Asthenic conditions 245
Risperidone General signs and symptoms NEC 128 Diabetes mellitus (incl subtypes) 713 General signs and symptoms NEC 223
Risperidone Dyskinesias and movement disorders NEC 121 Physical examination procedures 622 Death and sudden death 190
Ziprasidone Suicidal and self-injurious behavior 61 Neurological signs and symptoms NEC 319 Disturbances in consciousness NEC 41
Ziprasidone General signs and symptoms NEC 53 General signs and symptoms NEC 300 Ventricular arrhythmias and cardiac arrest 41
Ziprasidone Behavior and socialization disturbances 52 Anxiety symptoms 283 Neurological signs and symptoms NEC 35
Ziprasidone Neurological signs and symptoms NEC 47 Diabetes mellitus (incl subtypes) 281 Dyskinesias and movement disorders NEC 24
Ziprasidone Anxiety symptoms 41 Disturbances in consciousness NEC 280 Ischemic coronary artery disorders 23

Discussion

Overall, it was evident that both the frequencies and types of adverse events found in the adult population do not fit the distribution found in the pediatric or geriatric populations. As has been seen in prior studies, diabetes mellitus was frequently the most commonly reported adverse event in adults [10], but this was not the case for either the pediatric or geriatric populations. One possible explanation for this is that since adults are more likely than children to have impaired fasting glucose in the first place (often due to a longer exposure to certain physiolologic factors, such as obesity and a sedentary lifestyle), they may be more predisposed to developing this complication. On the other hand, “weight increase” was frequently a top-five adverse effect for the major antipsychotic medications in children, consistent with prior meta-analyses [11]. Children were also more likely to exhibit side effects, such as “aggression,” “abnormal behavior,” and “suicidality,” cognitive effects that may be seen more often in the developing brain. In particular, suicide attempts have previously been linked to antipsychotics in children with the AERS database [12]. For the geriatric population, neurological side effects, such as “confusional state” and “somnolence,” figured more prominently. This suggests that the elderly, who are predisposed to neurological problems, may be more severely affected by the neurological sequelae of antipsychotics. In fact, the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease (CATIE-AD) trial, studying elderly patients with Alzheimer's disease, showed that atypical antipsychotics were associated with worsening cognitive function comparable to an additional year's worth of cognitive decline compared to placebo [13].

Although we also analyzed differences in high-level terms between pediatric, adult, and geriatric populations, we realized that going to the next higher level grouping for MedDRA terms was not particularly illustrative. For instance, how does one distinguish “Neurological signs and symptoms” from “Disturbances in consciousness,” and what exactly constitutes “General signs and symptoms?” These were among the most commonly reported high-level terms.

Our analysis of the literature revealed that there were adverse events that frequently had reports in AERS; yet, these events were not commonly mentioned in the literature. In the adult population, amongst the top five adverse events for the seven major antipsychotics, only pancreatitis in patients taking quetiapine had fewer than five reports in the literature. The analyses for the pediatric and geriatric populations generated comparatively more adverse events that were not commonly found in the literature. The result for quetiapine in the geriatric population is interesting, given reports of its association with pneumonia [14].

The limitations of the FDA AERS database include the lack of information on the number of individuals taking the various antipsychotic medications in each age group, which could have served as a “denominator” in our study. Due to this lack of a denominator, when comparing the total number of adverse events across the pediatric, adult, and geriatric populations, it was difficult to determine whether variations in the relative distribution of adverse events between the three age groups was truly due to differences in the rate of adverse events rather than simply variations in prescription frequency. For instance, this could be related to prescription trends or when the medications were released. Fortunately, the issue of a denominator was not problematic when comparing the particular side effect profile between the three populations for any given drug. Another issue is the fact that the correlation of a particular medication with an adverse event does not necessarily prove causation. For instance, an individual who is prone to a particular adverse event may be more likely to take an antipsychotic. Another potential problem is recall bias, as a physician who knows a patient is taking a given drug may be more likely to report adverse events that are widely known to be associated with that drug. Nevertheless, the sheer volume of the AERS database and its vast scope make it a useful tool for studying drug-related adverse events.

Conclusions

Overall, we were able to show that there are significant differences in both the numbers and types of adverse events between the pediatric, adult, and geriatric populations. In addition, this study offers a number of drug and adverse event combinations for follow-up analysis. Given the fact that these medications were overwhelmingly tested on the adult population and are commonly prescribed off-label, it is imperative that clinicians remain mindful of these differences when prescribing these medications in populations for whom the drugs were never formally tested.


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Original article
peer-reviewed

Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations


Author Information

Hersh Sagreiya Corresponding Author

Radiology, University of Pittsburgh Medical Center

Yi-Ren Chen

Department of Neurosurgery, Stanford University Medical Center

Narmadan A. Kumarasamy

Radiology, Montefiore Medical Center

Karthik Ponnusamy

Orthopedics, Western University

Doris Chen

Internal Medicine, Stanford University Medical Center

Amar K. Das

Healthcare and Life Sciences, IBM T.J. Watson Research Center


Ethics Statement and Conflict of Interest Disclosures

Conflicts of interest: The authors have declared that no conflicts of interest exist.


Original article
peer-reviewed

Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations


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Original article
peer-reviewed

Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations

  • Author Information
    Hersh Sagreiya Corresponding Author

    Radiology, University of Pittsburgh Medical Center

    Yi-Ren Chen

    Department of Neurosurgery, Stanford University Medical Center

    Narmadan A. Kumarasamy

    Radiology, Montefiore Medical Center

    Karthik Ponnusamy

    Orthopedics, Western University

    Doris Chen

    Internal Medicine, Stanford University Medical Center

    Amar K. Das

    Healthcare and Life Sciences, IBM T.J. Watson Research Center


    Ethics Statement and Conflict of Interest Disclosures

    Conflicts of interest: The authors have declared that no conflicts of interest exist.

    Acknowledgements


    Article Information

    Published: February 26, 2017

    DOI

    10.7759/cureus.1059

    Cite this article as:

    Sagreiya H, Chen Y, Kumarasamy N A, et al. (February 26, 2017) Differences in Antipsychotic-Related Adverse Events in Adult, Pediatric, and Geriatric Populations. Cureus 9(2): e1059. doi:10.7759/cureus.1059

    Publication history

    Received by Cureus: December 18, 2016
    Peer review began: January 08, 2017
    Peer review concluded: February 19, 2017
    Published: February 26, 2017

    Copyright

    © Copyright 2017
    Sagreiya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 3.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    License

    This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

In recent years, antipsychotic medications have increasingly been used in pediatric and geriatric populations, despite the fact that many of these drugs were approved based on clinical trials in adult patients only. Preliminary studies have shown that the “off-label” use of these drugs in pediatric and geriatric populations may result in adverse events not found in adults. In this study, we utilized the large-scale U.S. Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) database to look at differences in adverse events from antipsychotics among adult, pediatric, and geriatric populations. We performed a systematic analysis of the FDA AERS database using MySQL by standardizing the database using structured terminologies and ontologies. We compared adverse event profiles of atypical versus typical antipsychotic medications among adult (18-65), pediatric (age < 18), and geriatric (> 65) populations. We found statistically significant differences between the number of adverse events in the pediatric versus adult populations with aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene, and between the geriatric versus adult populations with aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone (p < 0.05, with adjustment for multiple comparisons). Furthermore, the particular types of adverse events reported also varied significantly between each population for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (Chi-square, p < 10-6). Diabetes was the most commonly reported side effect in the adult population, compared to behavioral problems in the pediatric population and neurologic symptoms in the geriatric population. We also found discrepancies between the frequencies of reports in AERS and in the literature. Our analysis of the FDA AERS database shows that there are significant differences in both the numbers and types of adverse events among these age groups and between atypical and typical antipsychotics. It is important for clinicians to be mindful of these differences when prescribing antipsychotics, especially when prescribing medications off-label.

Introduction

While antipsychotic medications were initially approved based on clinical trials in adult populations, they are commonly prescribed “off-label” in pediatric and geriatric populations [1-2]. In addition, they are increasingly being prescribed to children. Between the 1993 - 1998 and 2005 - 2009 time periods, visits including a prescription for antipsychotics per 100 people increased from 0.24 to 1.83 for children, 0.78 to 3.76 for adolescents, and 3.25 to 6.18 for adults; moreover, antipsychotics were included in 31.1% of youth visits to psychiatrists [3]. While antipsychotics are among the most effective drugs for the treatment of schizophrenia, mania, or acute psychotic reactions, these medications are often prescribed to children and adolescents for non-FDA approved indications, such as disruptive behaviors and aggression [4-5]. Similarly, antipsychotics are frequently used in the elderly and are prescribed to more than a quarter of Medicare patients in nursing homes, with common conditions including dementia, delirium, and behavioral disturbances [2]. However, the use of these medications may result in unanticipated adverse events that are specific to the pediatric and geriatric populations [6]. In our study, we sought to elucidate the differences in adverse events between pediatric, adult, and geriatric populations using the FDA’s Adverse Events Reporting System (AERS), a database that has collected information about adverse events since 1998 [7]. AERS is the FDA’s primary tool for post-marketing adverse event surveillance, with over 250,000 adverse event reports annually [8]. A key strength of the AERS database is the ability to analyze a massive dataset and discover potentially new information regarding drug-related adverse events warranting further investigation. For instance, a recent paper probed the AERS database and found a potential link between amisulpride, cyamemazine, and olanzapine and torsadogenic risk [9]. Drug manufacturers are required to submit adverse event reports, while healthcare providers can voluntarily submit information.

Materials & Methods

We initially imported AERS quarterly data from January 2004 to September 2008 into the MySQL program (v.1.2.17) (Oracle Corp., Redwood Shores, CA). A table was created that mapped all the various drug names for antipsychotics to a generic name and a drug class (typical vs. atypical) using RxNorm (U.S. National Library of Medicine, Bethesda, MD) and Micromedex® (Truven Health Analytics, Greenwood Village, CO) (Table 1). Next, we joined this table with the AERS drug table (matching by DRUGNAME), the AERS demo table (matching by ISR, which stands for individual safety report), and the AERS REAC table (also matching by ISR). We first retrieved the total number of adverse events associated with each drug name, generic name, and drug class. Next, we created a yearage variable (which standardized all ages in AERS to be reported in years using the AGE and AGE_COD variables) as well as the GNDR_COD variable (which was reported as either “M” or “F”) in order to repeat this analysis on the following five subgroups: yearage < 18 (pediatrics), 18 ≥ yearage ≤ 65 (adults), and yearage > 65 (geriatrics), GNDR_COD = “M” (males), and GNDR_COD = ”F” (females).

Drug Name Generic Name Drug Class
Abilify Aripiprazole Atypicals
Aripiprazole Aripiprazole Atypicals
Chlorpromazine Chlorpromazine Typicals
Clozapine Clozapine Atypicals
Clozaril Clozapine Atypicals
Decazate Fluphenazine Typicals
Dozine Chlorpromazine Typicals
Fazalco Clozapine Atypicals
Fentazin Perphenazine   Typicals
Fluphenazine Fluphenazine Typicals
Fortunan Haloperidol Typicals
Geodon Ziprasidone Atypicals
Haldol Haloperidol Typicals
Haloperidol Haloperidol Typicals
Invega Paliperidone Atypicals
Kentace Haloperidol Typicals
Largactil Chlorpromazine Typicals
Loxapac Loxapine Typicals
Loxapine Loxapine Typicals
Loxitane Loxapine Typicals
Mellaril Thioridazine Typicals
Mesoridazine Mesoridazine Typicals
Moban Molindone Typicals
Moditen Fluphenazine Typicals
Navane Thiothixene Typicals
Noxene Thiothixene Typicals
Olanzapine Olanzapine Atypicals
Orap Pimozide Typicals
Ormazine Chlorpromazine Typicals
Permitil Fluphenazine Typicals
Perphenazine Perphenazine Typicals
Pimozide Pimozide Typicals
Primazine Promazine Typicals
Prolixin Fluphenazine Typicals
Promazine Promazine Typicals
Quetiapine Quetiapine Atypicals
Rideril Thioridazine Typicals
Risperdal Risperidone Atypicals
Risperidone Risperidone Atypicals
Serenace Haloperidol Typicals
Serentil Mesoridazine Typicals
Seroquel Quetiapine Atypicals
Sparine Promazine Typicals
Stelazine Trifluoperazine Typicals
Symbyax Olanzapine Atypicals
Thioridazine Thioridazine Typicals
Thiothixene Thiothixene Typicals
Thorazine Chlorpromazine Typicals
Trifluoperazine Trifluoperazine Typicals
Trilafon Promazine Typicals
Vesprin Triflupromazine Typicals
Ziprasidone Ziprasidone Atypicals
Zyprexa Olanzapine Atypicals

Next, for each drug, we computed the percent of antipsychotic-related adverse events that the drug represented in each population. We then used the z-test of proportions to compare this percent for each drug in the following categories: pediatrics vs. adults, adults vs. geriatrics, and males vs. females. This process was conducted separately for typical and atypical drugs. This resulted in a z-score and a p-value for each comparison, which was then adjusted using a Bonferroni correction for multiple comparisons, making the significance threshold 0.05/26 = 1.92 x 10-3.

Afterward, we retrieved the count of each individual adverse event associated with each generic drug, ordered by the frequency of occurrence in each population. We made sure not to include irrelevant or vague side effects in our top results, excluding terms such as “DRUG INTERACTION,” “ACCIDENTAL EXPOSURE,” and “ACCIDENTAL DRUG INTAKE BY CHILD.” In order to compare the frequencies of the different adverse events in the adult, pediatric, and geriatric populations, we conducted a Chi-square test. For each drug, we selected the top five adverse events in adults and added a sixth column that contained the sum of all other adverse events. We chose the top five since this minimized the number of cells in the Chi-square calculation that contained an expected value less than 5, which is not ideal for the Chi-square test. Next, we compared the frequency of these particular adverse events in the adult, pediatric, and geriatric populations using a 3 by 6 Chi-square table with 10 degrees of freedom, and we calculated p-values for each of seven major drugs—aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone—using the R statistical program (v2.12.2). We also used the MedRDA (Medical Directory for Regulatory Activities: International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland) hierarchy to map MedDRA Preferred Terms (the default FDA coding) to high-level terms and determined the frequency of the high-level terms in the three populations.

Next, we took the list of the top five adverse events for the seven drugs in the three populations and used Medical Subject Headings (MeSH terms) to evaluate how many times a particular drug-adverse event combination was indexed in PubMed for the three populations. For instance, for the side-effect “TREMOR” for aripiprazole in the geriatric population, we would have used the following search term: "aripiprazole"[Substance Name] AND ("Aged"[Mesh]) AND tremor. We then compared the number of reports in AERS and in the literature. For the drug, population, and adverse event combinations that had fewer than five reports in the literature, we manually examined the results to ensure their validity and highlighted the ones that we confirmed to have less than five reports.

Results

A summary of the populations we studied is shown in Table 2.

Category Value
Total number of patients 61,380
Mean age ± SD 45.7 ± 20.0
Patients where age < 18 3,578
Patients where age ≥ 18 and age 65 32,660
Patients where age > 65 7,260
Patients where age is not available 17,882
Male patients 27,783
Female patients 29,780
Gender NA (null, unknown, or not specified) 3,817

The percentage of antipsychotic-related side effects was often significantly different in the pediatric, adult, and geriatric populations for atypical and typical antipsychotics as shown in Tables 3-4.

Generic Name % of Adverse Events p-value (vs. Adults) Statistical Significance
Pediatrics Adults Geriatrics Pediatrics Geriatrics
Aripiprazole 25.9 9.8 4.8 0 0 Both
Clozapine 4.6 17.3 13.9 0 2.7e-14 Both
Olanzapine 16.1 26.0 25.6 0 0.23 Pediatrics
Paliperidone 0.6 0.6 0.2 0.43 3.5e-5 Geriatrics
Quetiapine 24.4 27.2 26.1 2.6e-5 0.019 Pediatrics
Risperidone 23.3 14.4 27.5 0 0 Both
Ziprasidone 5.1 4.6 1.9 0.077 0 Geriatrics
TOTALS 100.0 100.0 100.0  

Generic Name % of Adverse Events p-value (vs. Adults) Statistical Significance
Pediatrics Adults Geriatrics Pediatrics Geriatrics
Chlorpromazine 20.3 17.1 12.1 0.066 3.31e-6 Geriatrics
Fluphenazine 0.3 5.1 2.4 4.3e-5 4.39e-6 Both
Haloperidol 64.9 56.3 72.8 0.0011 0 Both
Loxapine 2.8 2.7 1.9 0.46 0.043 --
Mesoridazine 0.0 0.2 0.1 0.20 0.27 --
Molindone 0.9 0.3 0.6 0.017 0.018 --
Perphenazine 0.3 2.7 2.3 0.0038 0.19 --
Pimozide 3.4 1.6 1.3 0.0082 0.17 --
Promazine 0.6 2.8 0.1 0.0095 9.39e-10 Geriatrics
Thioridazine 5.5 3.9 3.4 0.070 0.20 --
Thiothixene 0.0 4.5 0.9 4.9e-5 1.24e-10 Both
Trifluoperazine 0.9 2.9 2.0 0.017 0.031 --
TOTALS 100.0 100.0 100.0  

Eight antipsychotics were associated with a significant difference in the number of adverse events in the pediatric vs. adult populations, including aripiprazole, clozapine, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and thiothixene. Ten antipsychotics were associated with a significant difference in the number of adverse events in the adult vs. geriatric populations, including aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, paliperidone, promazine, risperidone, thiothixene, and ziprasidone. When we compared the distributions of adverse events in the adult population to the pediatric and geriatric populations, Chi-square tests revealed that they were significantly different, as the p-values were 4.33e-32, 1.68e-92, 2.60e-35, 6.96e-106, 4.50e-124, 3.43e-65, and 1.35e-7, respectively, for aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone. Tables comparing the number of reports in the literature to those in the AERS database for the top five adverse events in seven major antipsychotics revealed some outliers in the three populations, as evidenced by the reports with less than five cases in the literature (Tables 5-6).

Generic Name Event Pediatrics N Pediatrics
Aripiprazole WEIGHT INCREASED 102
Aripiprazole TREMOR 86
Aripiprazole DYSTONIA 82
Aripiprazole SOMNOLENCE 63
Aripiprazole EXTRAPYRAMIDAL DISORDER 62
Aripiprazole OTHERS 3,087
Clozapine TACHYCARDIA 37
Clozapine GRANULOCYTOPENIA 32
Clozapine SOMNOLENCE 31
Clozapine WHITE BLOOD CELL COUNT DECREASED 26
Clozapine SEDATION 21
Clozapine OTHERS 1,069
Haloperidol SOMNOLENCE 35
Haloperidol TREMOR 23
Haloperidol EXTRAPYRAMIDAL DISORDER 18
Haloperidol MUSCLE SPASMS 15
Haloperidol NEUROLEPTIC MALIGNANT SYNDROME 14
Haloperidol OTHERS 770
Olanzapine WEIGHT INCREASED 106
Olanzapine AGGRESSION 69
Olanzapine SUICIDAL IDEATION 58
Olanzapine ABNORMAL BEHAVIOUR 46
Olanzapine COMPLETED SUICIDE 44
Olanzapine OTHERS 3,755
Quetiapine WEIGHT INCREASED 121
Quetiapine SUICIDAL IDEATION 80
Quetiapine TACHYCARDIA 74
Quetiapine CONVULSION 72
Quetiapine AGGRESSION 70
Quetiapine OTHERS 4,745
Risperidone AGGRESSION 112
Risperidone WEIGHT INCREASED 69
Risperidone CONVULSION 66
Risperidone SUICIDAL IDEATION 65
Risperidone ABNORMAL BEHAVIOUR 54
Risperidone OTHERS 4,015
Ziprasidone DYSTONIA 26
Ziprasidone SUICIDAL IDEATION 25
Ziprasidone DEPRESSION 20
Ziprasidone SUICIDE ATTEMPT 20
Ziprasidone WEIGHT INCREASED 19
Ziprasidone OTHERS 943

Generic Name Event Geriatrics N Geriatrics
Aripiprazole TREMOR 27
Aripiprazole NEUROLEPTIC MALIGNANT SYNDROME 22
Aripiprazole PARKINSONISM 21
Aripiprazole DEATH 18
Aripiprazole GAIT DISTURBANCE 15
Aripiprazole OTHERS 1,087
Clozapine DEATH 174
Clozapine PNEUMONIA 100
Clozapine PYREXIA 63
Clozapine SOMNOLENCE 50
Clozapine FALL 46
Clozapine OTHERS 3,117
Haloperidol AGITATION 78
Haloperidol CONFUSIONAL STATE 75
Haloperidol FALL 68
Haloperidol PYREXIA 67
Haloperidol DELIRIUM 62
Haloperidol OTHERS 5,196
Olanzapine FALL 175
Olanzapine CONFUSIONAL STATE 142
Olanzapine DIABETES MELLITUS 138
Olanzapine CEREBROVASCULAR ACCIDENT 107
Olanzapine PNEUMONIA 100
Olanzapine OTHERS 9,494
Quetiapine FALL 155
Quetiapine DEATH 111
Quetiapine CONFUSIONAL STATE 107
Quetiapine AGITATION 103
Quetiapine PNEUMONIA 91
Quetiapine OTHERS 7,377
Risperidone SOMNOLENCE 161
Risperidone DEATH 159
Risperidone CONFUSIONAL STATE 152
Risperidone FALL 135
Risperidone ASTHENIA 117
Risperidone OTHERS 8,770
Ziprasidone MYOCARDIAL INFARCTION 15
Ziprasidone COMA 15
Ziprasidone LOSS OF CONSCIOUSNESS 11
Ziprasidone SEDATION 11
Ziprasidone AGITATION 11
Ziprasidone OTHERS 706

Chi-square analysis was performed to compare the actual distribution of adverse events between the different populations for each drug. Seven commonly prescribed antipsychotics are presented in Table 7: aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone.

Generic Name Event Adults N Peds N Adults N Geriatrics p-Value
Aripiprazole DIABETES MELLITUS 11 288 10  
Aripiprazole WEIGHT INCREASED 102 235 13  
Aripiprazole INSOMNIA 11 227 12  
Aripiprazole TREMOR 86 177 27  
Aripiprazole ANXIETY 13 158 4  
Aripiprazole OTHERS 3,259 14,491 1,124 4.3e-32
Clozapine GRANULOCYTOPENIA 32 611 27  
Clozapine LEUKOPENIA 11 390 20  
Clozapine PYREXIA 16 376 63  
Clozapine DEATH 0 342 174  
Clozapine TACHYCARDIA 37 309 17  
Clozapine OTHERS 1,120 29,669 3,249 1.7e-92
Haloperidol DIABETES MELLITUS 0 205 8  
Haloperidol NEUROLEPTIC MALIGNANT SYNDROME 14 196 44  
Haloperidol SOMNOLENCE 35 148 41  
Haloperidol PYREXIA 10 147 67  
Haloperidol HYPERTENSION 2 128 12  
Haloperidol OTHERS 814 14,528 5,374 2.6e-35
Olanzapine DIABETES MELLITUS 42 2,197 138  
Olanzapine WEIGHT INCREASED 106 1,464 64  
Olanzapine HYPERTENSION 21 906 56  
Olanzapine PANCREATITIS 27 865 43  
Olanzapine DIABETES MELLITUS NON-INSULIN-DEPENDENT 6 720 21  
Olanzapine OTHERS 3,876 62,460 9,834 7.0e-106
Quetiapine DIABETES MELLITUS 39 2,066 55  
Quetiapine PANCREATITIS 16 871 28  
Quetiapine WEIGHT INCREASED 121 662 18  
Quetiapine SOMNOLENCE 70 528 79  
Quetiapine DIZZINESS 41 473 75  
Quetiapine OTHERS 4,875 48,314 7,689 4.5e-124
Risperidone DIABETES MELLITUS 20 614 34  
Risperidone WEIGHT INCREASED 69 390 15  
Risperidone DEPRESSION 46 327 41  
Risperidone SOMNOLENCE 47 292 161  
Risperidone NEUROLEPTIC MALIGNANT SYNDROME 19 262 37  
Risperidone OTHERS 4,180 32,300 9,206 3.4e-65
Ziprasidone DIABETES MELLITUS 4 243 3  
Ziprasidone WEIGHT INCREASED 19 173 2  
Ziprasidone ANXIETY 15 116 5  
Ziprasidone DEPRESSION 20 105 3  
Ziprasidone INSOMNIA 12 104 6  
Ziprasidone OTHERS 983 10,316 750 1.3e-7

The top five adverse events for less common drugs are listed in Table 8.

Generic Name Event Pediatrics N Event Adults N Event Geriatrics N
Chlorpromazine DRUG EXPOSURE DURING PREGNANCY 12 DIABETES MELLITUS 100 WEIGHT DECREASED 17
Chlorpromazine SOMNOLENCE 9 VOMITING 59 DIARRHOEA 16
Chlorpromazine AGGRESSION 7 NEUROLEPTIC MALIGNANT SYNDROME 52 DEHYDRATION 15
Chlorpromazine DRUG INEFFECTIVE 6 CONVULSION 51 PNEUMONIA 14
Chlorpromazine WEIGHT INCREASED 6 PYREXIA 50 SEPSIS 13
Fluphenazine ARRHYTHMIA 1 DIABETES MELLITUS 26 CONFUSIONAL STATE 6
Fluphenazine MYOCARDITIS 1 HYPERTENSION 22 URINARY TRACT INFECTION 5
Fluphenazine PYREXIA 1 WEIGHT INCREASED 17 SOMNOLENCE 5
Fluphenazine NA 0 HYPONATRAEMIA 17 SEDATION 5
Fluphenazine NA 0 HYPOTENSION 16 TACHYCARDIA 3
Loxapine PROTHROMBIN LEVEL DECREASED 3 PYREXIA 15 DYSPHAGIA 5
Loxapine CONGENITAL GENITOURINARY ABNORMALITY 2 SEPSIS 11 CONFUSIONAL STATE 4
Loxapine CRYPTORCHISM 2 AGITATION 10 DEPRESSED LEVEL OF CONSCIOUSNESS 4
Loxapine DRUG EXPOSURE DURING PREGNANCY 2 LACTIC ACIDOSIS 10 SOMNOLENCE 3
Loxapine RENAL CYST 2 BLOOD CREATINE PHOSPHOKINASE INCREASED 9 ANAEMIA 3
Mesoridazine NA 0 AGGRESSION 4 MALAISE 1
Mesoridazine NA 0 EXCESSIVE MASTURBATION 3 STOMATITIS 1
Mesoridazine NA 0 RASH PAPULAR 3 TARDIVE DYSKINESIA 1
Mesoridazine NA 0 SKIN ULCER 3 NA 0
Mesoridazine NA 0 RASH 2 NA 0
Molindone NEUROLEPTIC MALIGNANT SYNDROME 2 PRESCRIBED OVERDOSE 3 HAEMOGLOBIN DECREASED 3
Molindone MYOSITIS 1 CONVULSION 3 MYELOID LEUKAEMIA 3
Molindone PYREXIA 1 DIABETES MELLITUS NON-INSULIN-DEPENDENT 2 PLATELET COUNT DECREASED 3
Molindone VIRAL MYOSITIS 1 ANGER 2 WHITE BLOOD CELL COUNT INCREASED 3
Molindone RASH 1 ABDOMINAL DISTENSION 2 TARDIVE DYSKINESIA 3
Paliperidone NEUROLEPTIC MALIGNANT SYNDROME 10 GALACTORRHOEA 30 DYSPNOEA 4
Paliperidone HEADACHE 9 EXTRAPYRAMIDAL DISORDER 23 DEEP VEIN THROMBOSIS 3
Paliperidone CONFUSIONAL STATE 8 AKATHISIA 17 TREMOR 3
Paliperidone PALPITATIONS 8 OEDEMA PERIPHERAL 17 RENAL FAILURE 3
Paliperidone DYSTONIA 6 DYSTONIA 12 CONFUSIONAL STATE 2
Perphenazine NA 0 VOMITING 11 DRUG INEFFECTIVE 6
Perphenazine NA 0 COMPLETED SUICIDE 10 HYPOTENSION 5
Perphenazine NA 0 DIABETES MELLITUS 10 INSOMNIA 4
Perphenazine NA 0 DRUG INTERACTION 8 CEREBRAL INFARCTION 4
Perphenazine NA 0 DRUG INEFFECTIVE 8 AGRANULOCYTOSIS 3
Pimozide WEIGHT INCREASED 4 CARDIAC ARREST 12 COMA 4
Pimozide DIARRHOEA 4 SUICIDE ATTEMPT 8 MEDICATION ERROR 4
Pimozide RECTAL HAEMORRHAGE 4 DRUG INTERACTION 7 TOXIC SKIN ERUPTION 3
Pimozide SOMNOLENCE 3 OVERDOSE 6 THROMBOCYTOPENIA 3
Pimozide ANOREXIA 2 ANXIETY 6 FALL 2
Promazine NEONATAL DIABETES MELLITUS 1 DIABETES MELLITUS 33 DRUG INTERACTION 2
Promazine PREMATURE BABY 1 PANCREATITIS 15 METHYLMALONIC ACIDURIA 1
Promazine DEATH 1 MYOCARDIAL INFARCTION 15 MUSCLE RIGIDITY 1
Promazine DIAPHRAGMATIC HERNIA 1 BLOOD PRESSURE DECREASED 14 CONFUSIONAL STATE 1
Promazine PULMONARY HYPOPLASIA 1 MYOCARDITIS 14 PLATELET COUNT INCREASED 1
Thioridazine NAUSEA 8 HEADACHE 32 CONFUSIONAL STATE 9
Thioridazine ANOREXIA 8 DIZZINESS 29 HYPERGLYCAEMIA 8
Thioridazine VOMITING 5 DEPRESSION 25 ANXIETY 7
Thioridazine ACHOLIA 5 ANXIETY 24 BACK PAIN 7
Thioridazine AGGRESSION 5 WEIGHT DECREASED 22 DEPRESSION 6
Thiothixene NA 0 DIABETES MELLITUS 63 DYSPNOEA 4
Thiothixene NA 0 WEIGHT INCREASED 56 CEREBROVASCULAR ACCIDENT 3
Thiothixene NA 0 HEADACHE 33 NAUSEA 3
Thiothixene NA 0 PANCREATITIS 33 TARDIVE DYSKINESIA 3
Thiothixene NA 0 CHEST PAIN 31 ANTICHOLINERGIC SYNDROME 2
Trifluoperazine SEXUAL OFFENCE 1 DIABETES MELLITUS 32 CEREBROVASCULAR ACCIDENT 6
Trifluoperazine CONVULSION 1 INSOMNIA 16 CEREBRAL ATROPHY 5
Trifluoperazine DEPRESSION 1 DEPRESSION 13 TRANSIENT ISCHAEMIC ATTACK 5
Trifluoperazine INJURY 1 DIABETIC KETOACIDOSIS 12 TREMOR 5
Trifluoperazine MEDICATION ERROR 1 PANCREATITIS 12 MYOCARDIAL INFARCTION 4

The top five adverse events for the seven major antipsychotics mapped to MedDRA high-level terms are listed in Table 9.

Generic Event Pediatrics N Event Adults N Event Geriatrics N
Aripiprazole Neurological signs and symptoms NEC 196 Neurological signs and symptoms NEC 577 Neurological signs and symptoms NEC 56
Aripiprazole Dyskinesias and movement disorders NEC 172 Dyskinesias and movement disorders NEC 445 General signs and symptoms NEC 36
Aripiprazole Disturbances in consciousness NEC 143 Anxiety symptoms 420 Muscle tone abnormal 33
Aripiprazole Physical examination procedures 133 General signs and symptoms NEC 408 Dyskinesias and movement disorders NEC 33
Aripiprazole General signs and symptoms NEC 117 Physical examination procedures 402 Parkinson's disease and parkinsonism 29
Clozapine Disturbances in consciousness NEC 78 White blood cell analyses 1,222 General signs and symptoms NEC 193
Clozapine White blood cell analyses 56 Neutropenias 1,137 Death and sudden death 192
Clozapine Neutropenias 52 Disturbances in consciousness NEC 952 Disturbances in consciousness NEC 145
Clozapine Rate and rhythm disorders NEC 42 General signs and symptoms NEC 887 Lower respiratory tract and lung infections 121
Clozapine Neurological signs and symptoms NEC 39 Neurological signs and symptoms NEC 831 Lower respiratory tract infections NEC 117
Haloperidol Disturbances in consciousness NEC 51 Disturbances in consciousness NEC 471 Neurological signs and symptoms NEC 246
Haloperidol Medication errors due to accidental exposures 50 Neurological signs and symptoms NEC 425 Disturbances in consciousness NEC 162
Haloperidol Muscle tone abnormal 39 General signs and symptoms NEC 381 General signs and symptoms NEC 141
Haloperidol Dyssomnias 35 Breathing abnormalities 278 Ventricular arrhythmias and cardiac arrest 140
Haloperidol Dyskinesias and movement disorders NEC 33 Liver function analyses 274 Anxiety symptoms 126
Olanzapine Suicidal and self-injurious behavior 198 Diabetes mellitus (incl subtypes) 2,403 Disturbances in consciousness NEC 374
Olanzapine Physical examination procedures 150 Physical examination procedures 2,016 Neurological signs and symptoms NEC 355
Olanzapine Neurological signs and symptoms NEC 134 General signs and symptoms NEC 1,556 General signs and symptoms NEC 303
Olanzapine Behavior and socialization disturbances 130 Disturbances in consciousness NEC 1,551 Non-site specific injuries NEC 201
Olanzapine General signs and symptoms NEC 126 Neurological signs and symptoms NEC 1,312 Liver function analyses 182
Quetiapine Suicidal and self-injurious behavior 235 Diabetes mellitus (incl subtypes) 2,432 Neurological signs and symptoms NEC 331
Quetiapine Neurological signs and symptoms NEC 205 General signs and symptoms NEC 1,531 Disturbances in consciousness NEC 292
Quetiapine Physical examination procedures 178 Neurological signs and symptoms NEC 1,514 General signs and symptoms NEC 221
Quetiapine General signs and symptoms NEC 172 Disturbances in consciousness NEC 1,386 Non-site specific injuries NEC 181
Quetiapine Disturbances in consciousness NEC 170 Suicidal and self-injurious behavior 1,120 Circulatory collapse and shock 170
Risperidone Behavior and socialization disturbances 217 General signs and symptoms NEC 966 Disturbances in consciousness NEC 441
Risperidone Suicidal and self-injurious behavior 202 Disturbances in consciousness NEC 870 Neurological signs and symptoms NEC 351
Risperidone Neurological signs and symptoms NEC 194 Neurological signs and symptoms NEC 867 Asthenic conditions 245
Risperidone General signs and symptoms NEC 128 Diabetes mellitus (incl subtypes) 713 General signs and symptoms NEC 223
Risperidone Dyskinesias and movement disorders NEC 121 Physical examination procedures 622 Death and sudden death 190
Ziprasidone Suicidal and self-injurious behavior 61 Neurological signs and symptoms NEC 319 Disturbances in consciousness NEC 41
Ziprasidone General signs and symptoms NEC 53 General signs and symptoms NEC 300 Ventricular arrhythmias and cardiac arrest 41
Ziprasidone Behavior and socialization disturbances 52 Anxiety symptoms 283 Neurological signs and symptoms NEC 35
Ziprasidone Neurological signs and symptoms NEC 47 Diabetes mellitus (incl subtypes) 281 Dyskinesias and movement disorders NEC 24
Ziprasidone Anxiety symptoms 41 Disturbances in consciousness NEC 280 Ischemic coronary artery disorders 23

Discussion

Overall, it was evident that both the frequencies and types of adverse events found in the adult population do not fit the distribution found in the pediatric or geriatric populations. As has been seen in prior studies, diabetes mellitus was frequently the most commonly reported adverse event in adults [10], but this was not the case for either the pediatric or geriatric populations. One possible explanation for this is that since adults are more likely than children to have impaired fasting glucose in the first place (often due to a longer exposure to certain physiolologic factors, such as obesity and a sedentary lifestyle), they may be more predisposed to developing this complication. On the other hand, “weight increase” was frequently a top-five adverse effect for the major antipsychotic medications in children, consistent with prior meta-analyses [11]. Children were also more likely to exhibit side effects, such as “aggression,” “abnormal behavior,” and “suicidality,” cognitive effects that may be seen more often in the developing brain. In particular, suicide attempts have previously been linked to antipsychotics in children with the AERS database [12]. For the geriatric population, neurological side effects, such as “confusional state” and “somnolence,” figured more prominently. This suggests that the elderly, who are predisposed to neurological problems, may be more severely affected by the neurological sequelae of antipsychotics. In fact, the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease (CATIE-AD) trial, studying elderly patients with Alzheimer's disease, showed that atypical antipsychotics were associated with worsening cognitive function comparable to an additional year's worth of cognitive decline compared to placebo [13].

Although we also analyzed differences in high-level terms between pediatric, adult, and geriatric populations, we realized that going to the next higher level grouping for MedDRA terms was not particularly illustrative. For instance, how does one distinguish “Neurological signs and symptoms” from “Disturbances in consciousness,” and what exactly constitutes “General signs and symptoms?” These were among the most commonly reported high-level terms.

Our analysis of the literature revealed that there were adverse events that frequently had reports in AERS; yet, these events were not commonly mentioned in the literature. In the adult population, amongst the top five adverse events for the seven major antipsychotics, only pancreatitis in patients taking quetiapine had fewer than five reports in the literature. The analyses for the pediatric and geriatric populations generated comparatively more adverse events that were not commonly found in the literature. The result for quetiapine in the geriatric population is interesting, given reports of its association with pneumonia [14].

The limitations of the FDA AERS database include the lack of information on the number of individuals taking the various antipsychotic medications in each age group, which could have served as a “denominator” in our study. Due to this lack of a denominator, when comparing the total number of adverse events across the pediatric, adult, and geriatric populations, it was difficult to determine whether variations in the relative distribution of adverse events between the three age groups was truly due to differences in the rate of adverse events rather than simply variations in prescription frequency. For instance, this could be related to prescription trends or when the medications were released. Fortunately, the issue of a denominator was not problematic when comparing the particular side effect profile between the three populations for any given drug. Another issue is the fact that the correlation of a particular medication with an adverse event does not necessarily prove causation. For instance, an individual who is prone to a particular adverse event may be more likely to take an antipsychotic. Another potential problem is recall bias, as a physician who knows a patient is taking a given drug may be more likely to report adverse events that are widely known to be associated with that drug. Nevertheless, the sheer volume of the AERS database and its vast scope make it a useful tool for studying drug-related adverse events.

Conclusions

Overall, we were able to show that there are significant differences in both the numbers and types of adverse events between the pediatric, adult, and geriatric populations. In addition, this study offers a number of drug and adverse event combinations for follow-up analysis. Given the fact that these medications were overwhelmingly tested on the adult population and are commonly prescribed off-label, it is imperative that clinicians remain mindful of these differences when prescribing these medications in populations for whom the drugs were never formally tested.

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Hersh Sagreiya

Radiology, University of Pittsburgh Medical Center

For correspondence:
sagreiya@gmail.com

Yi-Ren Chen, M.D., M.P.H.

Department of Neurosurgery, Stanford University Medical Center

Narmadan A. Kumarasamy

Radiology, Montefiore Medical Center

Karthik Ponnusamy

Orthopedics, Western University

Doris Chen

Internal Medicine, Stanford University Medical Center

Amar K. Das

Healthcare and Life Sciences, IBM T.J. Watson Research Center

Hersh Sagreiya

Radiology, University of Pittsburgh Medical Center

For correspondence:
sagreiya@gmail.com

Yi-Ren Chen, M.D., M.P.H.

Department of Neurosurgery, Stanford University Medical Center

Narmadan A. Kumarasamy

Radiology, Montefiore Medical Center

Karthik Ponnusamy

Orthopedics, Western University

Doris Chen

Internal Medicine, Stanford University Medical Center

Amar K. Das

Healthcare and Life Sciences, IBM T.J. Watson Research Center