Journal of Psychopharmacology http://jop.sagepub.com/
Antipsychotics use in children and adolescents: An on-going challenge in clinical practice Carolina Schneider, David Taylor, Gil Zalsman, Sophia Frangou and Marinos Kyriakopoulos J Psychopharmacol published online 5 June 2014 DOI: 10.1177/0269881114533599 The online version of this article can be found at: http://jop.sagepub.com/content/early/2014/05/28/0269881114533599
Published by: http://www.sagepublications.com
On behalf of:
British Association for Psychopharmacology
Additional services and information for Journal of Psychopharmacology can be found at: Email Alerts: http://jop.sagepub.com/cgi/alerts Subscriptions: http://jop.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 5, 2014 What is This?
Downloaded from jop.sagepub.com at Harvard Library on June 16, 2014
533599 research-article2014
JOP0010.1177/0269881114533599Journal of PsychopharmacologySchneider et al.
Review
Antipsychotics use in children and adolescents: An on-going challenge in clinical practice Carolina Schneider1,2, David Taylor2,3, Gil Zalsman4,5, Sophia Frangou6 and Marinos Kyriakopoulos1,2,6
Journal of Psychopharmacology 1–9 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114533599 jop.sagepub.com
Abstract Antipsychotic medications (APs) are a well-established pharmacological treatment in adults with serious mental health problems. However, many adult mental health disorders have their origins and onset in childhood or adolescence. The understanding that neuropsychiatric conditions of childhood are in part biologically determined, led to an increase in the number of clinical trials supporting evidence on the efficacy of antipsychotic agents as first-line treatment for childhood psychotic disorders and therapeutic augmentation of nonpsychotic conditions. In recent years the use of antipsychotics in children and adolescents for neurodevelopmental, behavioural and psychiatric disorders has significantly increased while the age of prescription has decreased. These trends have not been matched by advances in the understanding of APs’ safety profile in this group of patients. It is therefore crucial that current and future practice is informed by up-to-date synthesis of the evidence and clinical guidelines about the use and monitoring of these treatments in paediatric populations, since the effectiveness of early therapeutic interventions in children can affect positively the long-term outcome.
Keywords Antipsychotic medication, children, adolescents, bipolar, schizophrenia, autism, adverse effects
Review of current evidence The common feature of most antipsychotic drugs is that they reduce dopaminergic neurotransmission, an action considered essential for their antipsychotic role. Currently available agents are divided into first generation antipsychotics (FGAs) and second generation antipsychotics (SGAs) mostly based on their side-effects profile, where the use of FGAs is more likely to cause extrapyramidal side-effects (EPS) than the use of SGAs. FGA drugs have the main property of blocking dopamine D2 receptors. The clinical efficacy appears to be correlated with a striatal D2 receptor occupancy of above 65%. SGAs are a heterogeneous group of agents that have complex pharmacologic entities, acting upon multiple dopamine receptors (D2, D1, D3, and D4) and multiple serotonin (5-HT) receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1D, among others) (Table 1). The therapeutic effect seems to be due not only to an acute effect in the postsynaptic overactive dopaminergic system, since the improvement of symptoms usually lasts several weeks and the receptor blockade is immediate. The most common adverse effects of FGAs are sedation, hypotension, Parkinsonism and abnormal involuntary movement disorders such as tardive dyskinesia (TD). In contrast, SGAs are most commonly associated with metabolic side effects such as weight increase and abnormal glucose and lipid metabolism which are associated with raised cardiovascular risk on longterm use.
APs prescription in children: A continuing increase trend Most APs are prescribed for children off-label. This can place children not only at a direct risk of under or overdosing but also at a delayed risk of long-term adverse effects. However, it has become increasingly common to use these medications to treat a variety of mental health disorders in children and adolescents, without this being supported by rigorous scientific data. A study of the prescribing trends in nine countries between the years 2000–2002, found that the increase in psychotropic prescribing in 1National
and Specialist Acorn Lodge Children’s Unit, South London and Maudsley NHS Foundation Trust, London, UK 2Institute of Psychiatry, King’s College London, London, UK 3Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK 4Division of Child and Adolescent Psychiatry, Tel Aviv University, Tel Aviv, Israel 5Molecular Imaging and Neuropathology Division, Columbia University, New York, NY, USA 6Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA Corresponding author: Marinos Kyriakopoulos, National and Specialist Acorn Lodge Inpatient Children’s Unit and Institute of Psychiatry, PO66, King’s College London, De Crespigny Park, London SE5 8AF, UK. Email: [email protected]
Downloaded from jop.sagepub.com at Harvard Library on June 16, 2014
Downloaded from jop.sagepub.com at Harvard Library on June 16, 2014
Relatively low risk of EPS
Reduced positive symptoms
+++
D2 PA +++ +++ + ++ – ++ +++ + +++ +++ Reduced positive symptoms; reduced negative symptoms; procognitive; antidepressant Unknown
D3
Unknown
+ + + ++ Reduced EPS; reduced hyperprolactinaemia; antidepressant; anxiolytic
+++ ++ + ++ +++
5HT1A
Unknown
+ ++++ + ++ + +++ ++++ + ++++ ++++ Reduced EPS; reduced hyperprolactinaemia
5HT2A
Cardiometabolic
++ ++++ ++ + + ++ ++ + ++ ++ Antidepressant
5HT2C
Unknown
+++ ++++ ++ ++ ++++ + +++ ++ ++ +++ Reduced circadian cycle; reduced negative symptoms; procognitive; antidepressant
5HT7
Dizziness; sedation; hypotension
++ +++ +++ +++ ++ ++ +++ +++ +++ ++ Reduced nightmares
α1
Cardiometabolic; constipation; sedation; dry mouth; blurred vision
Reduced EPS
Reduced EPS
Constipation; sedation; dry mouth; blurred vision
++
++
++
M3
++
++
+ +++
M1
5HT: serotonin; PA: partial antagonist; EPS: extrapyramidal side-effects. + Weak binding affinity (100>KiKiKi
Antipsychotics use in children and adolescents: An on-going challenge in clinical practice Carolina Schneider, David Taylor, Gil Zalsman, Sophia Frangou and Marinos Kyriakopoulos J Psychopharmacol published online 5 June 2014 DOI: 10.1177/0269881114533599 The online version of this article can be found at: http://jop.sagepub.com/content/early/2014/05/28/0269881114533599
Published by: http://www.sagepublications.com
On behalf of:
British Association for Psychopharmacology
Additional services and information for Journal of Psychopharmacology can be found at: Email Alerts: http://jop.sagepub.com/cgi/alerts Subscriptions: http://jop.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 5, 2014 What is This?
Downloaded from jop.sagepub.com at Harvard Library on June 16, 2014
533599 research-article2014
JOP0010.1177/0269881114533599Journal of PsychopharmacologySchneider et al.
Review
Antipsychotics use in children and adolescents: An on-going challenge in clinical practice Carolina Schneider1,2, David Taylor2,3, Gil Zalsman4,5, Sophia Frangou6 and Marinos Kyriakopoulos1,2,6
Journal of Psychopharmacology 1–9 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114533599 jop.sagepub.com
Abstract Antipsychotic medications (APs) are a well-established pharmacological treatment in adults with serious mental health problems. However, many adult mental health disorders have their origins and onset in childhood or adolescence. The understanding that neuropsychiatric conditions of childhood are in part biologically determined, led to an increase in the number of clinical trials supporting evidence on the efficacy of antipsychotic agents as first-line treatment for childhood psychotic disorders and therapeutic augmentation of nonpsychotic conditions. In recent years the use of antipsychotics in children and adolescents for neurodevelopmental, behavioural and psychiatric disorders has significantly increased while the age of prescription has decreased. These trends have not been matched by advances in the understanding of APs’ safety profile in this group of patients. It is therefore crucial that current and future practice is informed by up-to-date synthesis of the evidence and clinical guidelines about the use and monitoring of these treatments in paediatric populations, since the effectiveness of early therapeutic interventions in children can affect positively the long-term outcome.
Keywords Antipsychotic medication, children, adolescents, bipolar, schizophrenia, autism, adverse effects
Review of current evidence The common feature of most antipsychotic drugs is that they reduce dopaminergic neurotransmission, an action considered essential for their antipsychotic role. Currently available agents are divided into first generation antipsychotics (FGAs) and second generation antipsychotics (SGAs) mostly based on their side-effects profile, where the use of FGAs is more likely to cause extrapyramidal side-effects (EPS) than the use of SGAs. FGA drugs have the main property of blocking dopamine D2 receptors. The clinical efficacy appears to be correlated with a striatal D2 receptor occupancy of above 65%. SGAs are a heterogeneous group of agents that have complex pharmacologic entities, acting upon multiple dopamine receptors (D2, D1, D3, and D4) and multiple serotonin (5-HT) receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1D, among others) (Table 1). The therapeutic effect seems to be due not only to an acute effect in the postsynaptic overactive dopaminergic system, since the improvement of symptoms usually lasts several weeks and the receptor blockade is immediate. The most common adverse effects of FGAs are sedation, hypotension, Parkinsonism and abnormal involuntary movement disorders such as tardive dyskinesia (TD). In contrast, SGAs are most commonly associated with metabolic side effects such as weight increase and abnormal glucose and lipid metabolism which are associated with raised cardiovascular risk on longterm use.
APs prescription in children: A continuing increase trend Most APs are prescribed for children off-label. This can place children not only at a direct risk of under or overdosing but also at a delayed risk of long-term adverse effects. However, it has become increasingly common to use these medications to treat a variety of mental health disorders in children and adolescents, without this being supported by rigorous scientific data. A study of the prescribing trends in nine countries between the years 2000–2002, found that the increase in psychotropic prescribing in 1National
and Specialist Acorn Lodge Children’s Unit, South London and Maudsley NHS Foundation Trust, London, UK 2Institute of Psychiatry, King’s College London, London, UK 3Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK 4Division of Child and Adolescent Psychiatry, Tel Aviv University, Tel Aviv, Israel 5Molecular Imaging and Neuropathology Division, Columbia University, New York, NY, USA 6Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA Corresponding author: Marinos Kyriakopoulos, National and Specialist Acorn Lodge Inpatient Children’s Unit and Institute of Psychiatry, PO66, King’s College London, De Crespigny Park, London SE5 8AF, UK. Email: [email protected]
Downloaded from jop.sagepub.com at Harvard Library on June 16, 2014
Downloaded from jop.sagepub.com at Harvard Library on June 16, 2014
Relatively low risk of EPS
Reduced positive symptoms
+++
D2 PA +++ +++ + ++ – ++ +++ + +++ +++ Reduced positive symptoms; reduced negative symptoms; procognitive; antidepressant Unknown
D3
Unknown
+ + + ++ Reduced EPS; reduced hyperprolactinaemia; antidepressant; anxiolytic
+++ ++ + ++ +++
5HT1A
Unknown
+ ++++ + ++ + +++ ++++ + ++++ ++++ Reduced EPS; reduced hyperprolactinaemia
5HT2A
Cardiometabolic
++ ++++ ++ + + ++ ++ + ++ ++ Antidepressant
5HT2C
Unknown
+++ ++++ ++ ++ ++++ + +++ ++ ++ +++ Reduced circadian cycle; reduced negative symptoms; procognitive; antidepressant
5HT7
Dizziness; sedation; hypotension
++ +++ +++ +++ ++ ++ +++ +++ +++ ++ Reduced nightmares
α1
Cardiometabolic; constipation; sedation; dry mouth; blurred vision
Reduced EPS
Reduced EPS
Constipation; sedation; dry mouth; blurred vision
++
++
++
M3
++
++
+ +++
M1
5HT: serotonin; PA: partial antagonist; EPS: extrapyramidal side-effects. + Weak binding affinity (100>KiKiKi
