Safety and Efficacy Pharmacogenomics in Pediatric ...

Safety and Efficacy Pharmacogenomics 

in Pediatric Psychopharmacology 

Christopher A. Wall, MD, Catherine Oldenkamp, MMSII, and Cosima Swintak, MD 

ABSTRACT 

Historically, clinicians have had few resources beyond empiric tools 

derived from population-based treatment algorithms and patient/ 

family interviews to inform the “best choice” for psychopharmacolog- 

ic intervention. Previously unappreciated interindividual variance in 

activity of cytochrome P450 enzymatic activity can lead to abnormal 

metabolism of many psychotropics and poor outcomes. Fortunately, 

advances in our understanding and application of psychiatric phar- 

macogenomic information have the potential to improve the quality of 

medical care for children at the level of the individual prescription. 

INTRODUCTION 

A large number of children and adolescents presenting for 

health care are affected by mental illness and many require 

psychotropic medications as a component of their overall 

care. 1,2 Despite increasing choices in medication management, 

many of these patients still experience poor outcomes 

related to inadequate medication response and significant 

adverse drug events (ADEs). 3 Given ongoing shortages in the 

specialty of child and adolescent psychiatry, 4 the considerable 

challenge of prescribing psychotropics in the pediatric 

population is often managed by adult psychiatrists, family 

physicians, and pediatricians. In considering whether a 

medication is the “right” one for a given patient, all clinicians 

must weigh not only issues such as the potential for side 

effects, family responses to similar psychotropic medications, 

and the nature and intensity of the patient’s illness, but also 

psychosocial concerns. This is a process which is complicated 

by the knowledge that an incorrect choice could result in 

Primary Psychiatry 

53 

intolerable side effects, poor efficacy, and ultimately—perhaps 

most importantly—a negative view towards medication 

that may have proved helpful. Lack of efficacy and ADEs are 

frequently cited as reasons for noncompliance in pediatric 

psychopharmacology. 

Currently, children who are treated without the benefit of 

individualized molecular genotyping have only a 60% chance 

of successful long-term treatment. 5 Fortunately, advances in 

our understanding and application of individual pharmacogenetic 

profiles have the potential to improve the quality 

of medical care for children at the level of the individual 

prescription. 6 Pickar 7 has suggested that there is no specialty 

where the need for pharmacogenetics seems more compelling 

than for psychiatry. Psychiatric pharmacogenomics is 

an emerging tool to assist clinicians in developing strategies 

to personalize treatment and tailor therapy to individual 

patients, with the goal of optimizing efficacy and safety 

through better understanding of genetic variability and its 

influence on drug response. This article provides discussion 

of the role emerging pharmacogenomic advancement is 

Dr. Wall is instructor of psychiatry and consultant in child psychiatry and Dr. Swintak is instructor in psychiatry and senior associate consultant in child psychiatry, both in the Department of Psychiatry and 

Psychology at the Mayo Clinic in Rochester, Minnesota. Ms. Oldenkamp is a medical student at the Mayo Medical School in Rochester. 

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest. 

FOCUS POINTS 

CLINICAL FOCUS 

Primary Psychiatry. 2010;17(5):53-58 

• Advances in pharmacogenomics have the potential to 

improve the quality of medical care for children at the level 

of the individual prescription. 

• Nearly 80% of all drugs in use today, along with most psychotropics, 

are metabolized via testable metabolic pathways. 

• Children and adolescents with metabolic polymorphisms 

may be at greater risk for adverse drug events than children 

with normal metabolism. 

• Pediatric psychotropic prescribers must consider treatmentresistant 

patients as potential abnormal metabolizers. 

Please direct all correspondence to: Christopher A. Wall, MD, Instructor of Psychiatry, Consultant–Child Psychiatry, Dept of Psychiatry and Psychology, Mayo Clinic, 200 1st St, SW, Rochester, MN 55905; 

Tel: 507-284-3352; Fax: 507-533-5353; E-mail: wall.chris@mayo.edu. 

© MBL Communications Inc. May 2010

C.A. Wall, C. Oldenkamp, C. Swintak 

playing in the clinical practice of individualized psychopharmacology: 

moving away from “trial and error” prescriptions 

to individualized prescribing. The article also highlights the 

growing literature and adoption of pharmacogenomic principles 

guiding modern psychotropic prescribing practices 

focusing on the pediatric population. 

BACKGROUND OF PSYCHIATRIC 

PHARMACOGENOMICS 

Psychiatric pharmacogenomics is the study of how gene 

variations influence the responses of a patient to treatment 

with psychotropics. The most commonly studied cytochrome 

P450 (CYP) enzymes include 2D6, 2C19, and 2C9. 

Polymorphisms and gene duplications in these enzymes 

account for the most frequent variations in phase I metabolism 

of drugs since nearly 80% of all drugs in use today, along 

with most psychotropics (Tables 1 and 2), 8 are metabolized 

via these pathways. 9 It should also be noted that genetics may 

account for 20% to 95% percent of variability in drug disposition 

and effects. 10 

Historic and current literature divides metabolic phenotypes 

into four basic categories. These categories presented 

from least to most efficient metabolism are as follows: poor 

metabolism (PM; essentially no metabolism at a given 

enzyme pathway), intermediate metabolism (IM), extensive 

TABLE 1 

ANTIDEPRESSANT METABOLISM BY CYP ENZYME 8 

CYP 

Enzyme 

Primarily 

Metabolized 

2D6 desipramine 

doxepin 

fluoxetine 

nortriptyline 

paroxetine 

venlafaxine 

2C19 amitriptyline 

citalopram 

clomipramine 

escitalopram 

Substantially 

Metabolized 

amitriptyline 

bupropion 

duloxetine 

imipramine 

mirtazapine 

trazodone 

doxepin 


moclobemide 

notriptyline 

sertraline 

1A2 fluvoxamine clomipramine 

duloxetine 


2C9 None amitriptyline 

fluoxetine 

Minimally 

Metabolized 

citalopram 

escitalopram 

fluvoxamine 


venlafaxine 

amitriptyline 

mirtazapine 


Mrazek D. Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010. 

Reprinted with permission from Oxford University Press. Copyright 2010. 

CYP=cytochrome P450. 

Wall CA, Oldenkamp C, Swintak C. Primary Psychiatry. Vol 17, No 5. 2010. 

metabolism (EM; essentially “normal” metabolism), and 

ultra-rapid metabolism (UM). For the purpose of discussion, 

this article will highlight safety and efficacy concerns related 

to the 15% to 25% of pediatric patients that are either PM 

or UM metabolizers. 11 

SAFETY AND EFFICACY IN ABNORMAL 

METABOLIZERS 

The two primary tenets considered in all pediatric prescriptions 

are safety and efficacy, and both can be more precisely 

addressed through pharmacogenomics. “Safety pharmacogenomics” 

aims to avoid ADEs and side effects by identifying 

individuals who are likely to have difficulty with certain 

medications due to either increased activity of an enzymatic 

pathway (UMs), or lack of activity (PMs). “Efficacy pharmacogenomics” 

attempts to predict an individual’s likely response 

to a medication at the outset of treatment. 12 

Interindividual variance of activity of CYP enzymes can lead 

to abnormal metabolism of most antidepressants (Table 1) and 

antipsychotics (Table 2). These medications have been associated 

with a variety of ADEs, ranging from milder side effects, 

such as activation, irritability, sexual dysfunction, and sedation, 

to more significant ADEs, such as weight gain, extrapyramidal 

symptoms, metabolic syndrome, hyperprolactinemia, 

manic-induction, neuroleptic malignant syndrome, and even 

suicidality. 13 Children and adolescents with polymorphisms 

leading to abnormal drug metabolism may be at greater risk for 

some of these ADEs than children with normal metabolism, as 

medications administered at normal therapeutic doses to poor 

metabolizers may result in toxicity, and consequently ADEs. 

Conversely, UMs may not attain therapeutic plasma levels on 

typical therapeutic doses of medications and the treatment may 

TABLE 2 

ANTIPSYCHOTIC METABOLISM BY CYP ENZYME 8 

CYP 

Enzyme 

Primarily 

Metabolized 

2D6 chlorpromazine 

haloperidol 

perphenazine 

risperidone 

thioridazine 

Substantially 

Metabolized 

aripiprazole 

olanzapine 

Minimally 

Metabolized 

clozapine 

quetiapine 

ziprasidone 

2C19 None clozapine thioridazine 

1A2 clozapine 

olanzapine 

chlorpromazine haloperidol 

thioridazine 

Mrazek D. Psychiatric Pharmacogenomics. New York, NY: Oxford University Press; 2010. 

Reprinted with permission from Oxford University Press. Copyright 2010. 

CYP=cytochrome P450. 


Primary Psychiatry 54 


fail or lead to rapid conversion of prodrug to potentially toxic 

active metabolites. 

Table 3 13-51 includes a list of ADEs that have been linked to 

abnormal metabolism of psychotropics by at least one study 

involving abnormal metabolizers. As pharmacogenomic testing 

is a relatively new technology, not many studies have been 

performed investigating these links, but identifying the at-risk 

population in advance could do much to positively affect 

quality of life, increase compliance with medications, and 

even circumvent death in rare cases. Pharmacogenomic testing 

has the potential to offer a more complete, individualized 

risk profile enabling tailored choices of medication with doses 

appropriately adjusted for individual metabolism and advanced 

screening for the propensity of certain undesirable effects. 

SAFETY AND EFFICACY IMPLICATIONS 

IN POOR METABOLISM 

Weight Gain and Metabolic Syndrome 

There is no doubt that weight gain can be detrimental to a 

young person’s physical and mental health and can exacerbate 

problems with self-esteem during all developmental stages. 

Obesity, which is common among schizophrenic patients, 52 

may be further exacerbated by antipsychotics. It has been shown 

that decreased metabolism due to variations in several CYP 

genes may contribute to a patient’s risk profile while taking an 

antipsychotic. For example, decreased metabolism at CYP1A2, 

which is known to be involved in the metabolism of some antipsychotics, 

is associated with increased risk for weight gain and a 

TABLE 3 

ADVERSE EFFECTS ASSOCIATED WITH ABNORMAL METAB- 

OLISM 13-51 

Reduced metabolism (ie, poor) Increased metabolism (ie, ultrarapid) 

EPS 14-22 Opioid toxicity 23-33 

Tardive dyskinesia 14,34-36 Nausea 37 

Oversedation 38-40 Paradoxical excitation 41 

Cardiovascular complications 

(ie, tachycardia, hypertension, 

hypotension) 46,47 

Weight gain 46,47 Suicidality 13 

Neuroleptic malignant syndrome 48-50 

Serotonin syndrome 51 

Suicidality 22,51 

EPS=extrapyramidal symptoms. 

Treatment nonresponse 43-45 


Safety and Efficacy Pharmacogenomics in Pediatric Psychopharmacology 

cluster of clinical features including increased visceral adiposity, 

hyperglycemia, hypertension, and dyslipidemia known as “metabolic 

syndrome.” 53 Prevalence of metabolic syndrome is higher 

in women than it is in men as demonstrated in the Clinical 

Antipsychotic Trials of Intervention Effectiveness schizophrenia 

trial. 53 Lower activity of CYP1A2 may also contribute to the 

risk for metabolic syndrome by leading to increased serum 

concentrations of antipsychotics at standard doses. Children, 

especially young females, may be more susceptible to weight 

gain while on antipsychotics, 53-55 and weight gain may lead to 

noncompliance and subsequent relapse. 52-56 

All of this evidence suggests that pediatric patients are likely 

to be at increased risk of weight gain and metabolic syndrome if 

carrying polymorphisms associated with decreased or absent 1A2 

activity. Identifying poor metabolizers at this and other genes 

associated with atypical antipsychotic metabolism could allow a 

physician to be better informed of all risks when prescribing, and 

heighten awareness related to early signs of metabolic syndrome 

or weight gain. This may be especially pertinent to young female 

patients, who appear to carry the most risk. 

Extrapyramidal Symptoms 

Extrapyramidal symptoms (EPS) are frequent and serious 

acute adverse reactions to antipsychotics. These symptoms 

include pseudoparkinsonism, acute dystonia, akathisia, and 

tardive dyskinesia, 34 which may be permanent even after 

removal of the drug. 

Several hypotheses and studies indicate that PM at CYP2D6, 

which metabolizes several of the typical and atypical psychotropics, 

may increase the risk of developing EPS. Poor 

CYP2D6 metabolizers are likely to have higher than average 

plasma concentrations of neuroleptics with an increased risk 

for developing EPS, including tardive dyskinesia. 14,34,57-59 PM 

or inhibition of CYP2D6 may be linked to the induction of 

EPS. CYP2D6 in the brain is involved in the metabolism of 

dopamine and has a possible functional association with the 

dopamine transporter. 59,60 Several selective serotonin reuptake 

inhibiters and tricyclic antidepressants inhibit CYP2D6, as do 

a number of non-psychotropic drugs such as quinidine. Methy 

lphenyltetrahydropyridine, a dopamine neurotoxin able to produce 

Parkinsonism, is metabolized by 2D6 and is also a 2D6 

inhibitor. Vandel and colleagues 59 concluded that inhibition of 

CYP2D6 may be involved in the genesis of EPS observed in 

treatment with 2D6 substrate psychotropics. 

It follows that poor CYP2D6 metabolizers may be at increased 

risk for EPS while on certain antidepressants due to high plasma 

levels. 59 Indeed, it has been shown that there is a significant association 

between EPS and the CYP2D6*4 and CYP2D6*6 polymorphisms 

that are both associated with the poor metabolizer 

phenotype. 61,62 Furthermore, there may be a relationship between 

the degree of impaired CYP2D6 activity and the severity of EPS 

during neuroleptic treatment. 34 One study 14 demonstrating that 




the development of EPS or tardive dyskinesia while on antipsychotic 

medication is significantly more frequent among PMs 

than among matched IM and EM patients, also found a significantly 

higher prevalence of noncompliance among the same PM 

patients. These findings highlight the importance of identifying 

those at greater risk for experiencing these serious ADEs. 

Neuroleptic Malignant Syndrome 

Neuroleptic malignant syndrome (NMS) is a life-threatening 

ADE associated with antipsychotics, antidepressants, and 

other psychotropics. Signs of NMS include hyperthermia, 

EPS, altered consciousness, fluctuating blood pressure, incontinence, 

and dyspnea. 48,63,64 While some studies were unable to 

find a significant link between reduced function of CYP2D6 

and NMS, 65,66 more recent case studies suggest pharmacogenomic 

factors cannot yet be excluded as risk factors for this 

serious condition. In two separate case studies, four patients 

who developed NMS were later determined to have mutations 

in CYP2D6 conferring the PM phenotype. 48 It was concluded 

that while not all NMS patients have this poor metabolizer 

phenotype, poor metabolizers at CYP2D6 may be at increased 

risk for developing NMS. 49 

Hyperprolactinemia 

Conventional antipsychotics and certain atypical antipsychotics, 

such as risperidone, can cause significant elevations 

in prolactin. 53 For risperidone, increases in prolactin levels are 

dose related. 53,67 Though no studies have yet been conducted 

to show a link between PM phenotypes and ADEs related to 

hyperprolactinemia, this link remains not only possible, but an 

important consideration in the pediatric population. Amongst 

other potential developmental concerns, complications from 

early hyperprolactinemia may include bone loss, which in turn 

could lead to significant consequences upon reaching adulthood. 

Furthermore, if this increase in prolactin is dose related, PMs 

may have elevated risk as they may experience higher serum 

concentrations of poorly metabolized medication. 

Additional Considerations 

Prescribers should also bear in mind that over sedation, 

postural hypotension, and cardiovascular complications may 

be additional significant concerns in poor metabolizers. 68 

Likewise, as clinicians follow their natural tendency to optimize 

dosing in their treatment of psychiatric symptoms, it may 

be helpful to remember that, in the PM population, so called 

“somatic symptoms” associated with psychiatric diagnoses 

(and subsequent treatment) may in fact be medication intolerance 

exacerbated by dose titration. Without knowledge of the 

patient’s metabolic phenotype, the clinician must “guess” as to 

the cause of these symptoms and may incorrectly conclude that 

the patient is just “anxious” or “dramatic.” Furthermore, the 

clinician must also wonder whether or not the patient will be 

able to adequately tolerate the next medication choice. 

SAFETY AND EFFICACY IMPLICATIONS 

IN ULTRA-RAPID METABOLISM 

UMs present their own set of treatment challenges as they may 

not attain therapeutic plasma levels on normal doses of medications, 

and thus treatment may have a higher propensity to fail. 69 

For example, a recent Swedish autopsy study 13 found that among 

those who died of suicide, there was a higher number carrying 

>2 active CYP2D6 genes (UM phenotype) as compared with 

those who died of natural causes. Postulated explanations for this 

finding include accumulation of higher levels of metabolites at a 

faster rate which is a known risk of UM. This buildup may lead 

to adverse drug reactions if the metabolite is active or toxic. It 

could also be argued that in this population, UMs did not reach 

the desired therapeutic concentration of their prescribed medications 

and thus had not been treated effectively. This hypothesis 

is supported by Kawanishi and colleagues 43 who found UMs 

as more likely to fail to respond to antidepressants. The ultrarapid 

metabolizers in the study also had the worst scores on the 

Hamilton Rating Scale for Depression leading the authors to 

conclude that ultra rapid metabolism may be a risk factor for 

persistent mood disorders. 

Case studies in UMs suggest that diphenhydramine may be 

converted to a compound which causes paradoxical excitation 

due to the abnormally high CYP2D6 activity. 41 More serious 

consequences might be seen in children treated with other 

medications like codeine whose ultra-rapid conversion might 

result in toxic accumulation of morphine leading to death. 23 

It follows that UMs could be at increased risk of ADEs from 

higher levels of toxic or active metabolites from psychotropics. 

DISCUSSION 

To date, much of the available literature on pharmacogenomic 

testing in the pediatric population has focused on the spectrum 

of efficacy related to cancer treatments. 70-75 Impressive results in 

leukemia remission rates have been described as partly due to 

advancements in pharmacogenomically derived individualized 

prescribing practices. Cheok and colleagues 70 highlighted the 

progress made in the treatment of acute lymphoblastic leukemia 

in children noting the disease as being lethal 4 decades ago to 

current cure rates exceeding 80%. This progress is largely due to 

the optimization of existing treatment modalities rather than the 

discovery of new antileukemic agents. The literature regarding 

the pharmacogenomics of asthma treatment and research design 

has also been quite active in the pediatric population in the past 

few years. 76-83 In both cancer and asthma research, there are clear 



outcomes and endpoints to define treatment response and the 

role that interindividual variability plays. 

Historically, the process of initiating psychopharmacologic 

agents in the child and adolescent population has been 

empirically based and one in which the clinician considers 

many variables including age, gender, access to health care, 

and ability to remain compliant with the proposed treatment. 

Frequently factored into this consideration are quasi-genetic 

questions relating to family history of illness as well as family 

history of medication response. Until very recently, the use of 

family history has been the only tool available to better understand 

genetic makeup and its resultant interplay with efficacy 

and ADEs. In fact, as early as the 19th century, Holmes 84 

commented that, “All medications are directly harmful; the 

question is whether they are indirectly beneficial.” Fortunately, 

unlike in Holmes’ day, we now have the potential capability to 

resolve that very question; pharmacogenomic testing can help 

determine in advance whether an individual will respond favorably. 

Ongoing central nervous system maturation coupled with 

an increased risk for ADEs makes the utility of this advance 

most relevant in pediatric psychopharmacology. 

Though most prescribing in pediatric psychiatry is still off label, 

treatment algorithms do currently exist for most classes of psychotropics. 

Unfortunately, none of these algorithms base their recommendations 

on psychiatric pharmacogenomics. Furthermore, 

since dosing recommendations are based on “normal” metabolizers, 

they do not include the estimated 15% to 25% of the population 

who is either UMs (and therefore at much higher risk for 

resultant noncompliance due to never reaching therapeutic and/or 

beneficial levels) or poor with non-compliance resulting from 

ADEs. These outliers, who frequently end up in treatment-resistant 

categories of patients, might have entirely different outcomes 

if medication management were tailored to their genetic—and 

therefore most fundamental—needs. 

When considering the “stakes” involved in the early patientphysician-family 

relationship, it is clear that prescribing with 

improved confidence, and less risk of ADEs, will pay significant 

dividends. For example, if a clinician thoughtfully considers 

not only the symptoms involved in the patient’s illness 

process, but also the likelihood that the patient will experience 

difficulties with certain medications, the patient and family 

cannot help but be appreciative of the efforts involved at defining 

their particular risks. This transparency of process and subsequent 

conversations about the role for medications will allow 

for greater trust and a sense of improved objectivity. 

Widespread adoption of pharmacogenomic testing will be 

hampered by several factors including costs, limited sample 

sizes in research reports, and ingrained practice habits fueled by 

understandable skepticism and access challenges. Each of these 

issues will need to be individually addressed and overcome in the 

foreseeable future. Several academic medical centers are incorporating 

this form of testing into the comprehensive biopsycho- 

Safety and Efficacy Pharmacogenomics in Pediatric Psychopharmacology 

social workup and results appear promising. 11,85 Today, the cost 

of the genotyping of a single gene varies between $300–$700 

depending upon the complexity of the variants that are being 

identified. Fortunately, panels of informative genes can now be 

ordered for between $800–$1,500. With the rapid improvement 

in sequencing technologies that is now occurring, these costs will 

inevitably decrease in the near future. 

As psychiatric illnesses are increasingly recognized and 

treated in the pediatric population, clinicians now have access 

to an emerging set of pharmacogenomic principles to guide 

their prescribing practices. The primary principle is to use 

pharmacogenomic testing to increase the safety of psychotropics. 

A second principle is to use testing to identify medications 

that are unlikely to be effective. The ultimate goal of pharmacogenomic 

testing is to find the “right medication” on the first 

try. As pharmacogenomic testing becomes more sophisticated, 

it will be possible to abandon “trial and error” strategies and 

begin to provide individualized care utilizing metabolic and 

receptor pharmacogenomics. Using composite data, clinicians 

will have an unprecedented degree of molecular information 

available to help them choose effective medication-based treatments 

while minimizing the potential for ADEs. 

CONCLUSION 

As clinicians continue to treat pediatric patients with psychotropics, 

every relevant clinical observation and laboratory 

assessment should be considered to increase the likelihood 

of achieving remission of symptoms with minimal ADEs. 

Reviewing the results of pharmacogenomic testing prior to 

writing an initial prescription now provides clinicians useful 

individualized data that can be reviewed with the patient and 

family to inform them about the role that metabolism may 

play in treatment response as well as the possibility of ADEs. It 

is the authors’ belief that pharmacogenomic testing has a significant 

role in modern psychopharmacologic practice and that 

the associated expenses are already outweighed by the potential 

benefits of more individualized prescriptions. PP 

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