10 - Chapter 5 Prescribing in children and adolescents

01 - Principles of prescribing practice in childho
Principles of prescribing practice in childhood and adolescence
The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor,
Thomas R. E. Barnes and Allan H. Young.
© 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd.
Chapter 5
Principles of prescribing practice in childhood and adolescence
Diagnosis can be difficult in children and comorbidity is very common. Treatment
should generally target key symptoms rather than specific conditions. While a working
diagnosis is beneficial to frame expectations and help communication with patients
and parents, it should be kept in mind that it could take some time for the illness to
evolve.1
Differences in pharmacokinetics and pharmacodynamics compared with adults can
explain the more pronounced or unforeseen adverse reactions to medication in the
young, as well as the differences in ­dose–­effect relationships compared with those in
adults.2
■
■Start low, go slow and monitor
Depending on the age, dose starts lower than in adults or may be calculated in mg/kg
per day terms.1,2 Titration of dose should proceed slowly, aiming for the minimum
dose that adequately controls symptoms and has minimum adverse reactions. Regular
reviewing of efficacy and tolerability should guide if treatment is necessary and
requires continuation.
■
■Polypharmacy in the severely ill
Monotherapy is ideal. However, childhood-­onset illness can be severe and may
require treatment with psychosocial approaches in combination with more than one
medication.1 Co-­prescribing of medication for different disorders or symptoms is
common. This complicates the interpretation of efficacy of each medicine1 and
requires care with drug interactions and dose adjustments.
■
■Adequate treatment duration
Children are generally relatively more ill than their adult counterparts and will often
require longer periods of treatment before responding. An adequate trial of treatment
for those who are admitted for in-­patient care may well be 8 weeks or more for
depression or schizophrenia.
Prescribing in children
and adolescents
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■
■Change one drug at a time
Ideally changes should be made to one drug at a time and, if possible, remove a drug
when adding a new one.
■
■Monitor outcome in more than one setting
For symptomatic treatments (such as stimulants for attention deficit hyperactivity or
ADHD), bear in mind that the expression of problems may be different in different
settings (e.g. home and school). For example, a dose titrated against parent reports
may be too high for the daytime at school.
■
■Educate the child and parents on the treatment
For some, the need for medication will be life-­long. The first experiences with
­medications are crucial to long-­term outcomes and adherence. Education regarding
the target symptoms of the medication, likely adverse reactions and medication
adherence should be addressed. Provide information on the monitoring required and
how to identify adverse reactions. Patients and their guardians should be encouraged
to ask for changes to their treatment regimen where they consider them ineffective or
poorly tolerated.
■
■Review long-­term treatment
As children develop and grow through adolescence, dose changes may be required
and adverse reactions may emerge or wane.
■
■Transition from paediatric to adult services
It is essential that continuity of care is not lost when moving from paediatric to adult
services as this can be distressing and increase the risk of relapse. Planning and
­co-­ordination should start at an early stage to achieve a smooth transition.3
■
■Technical aspects of paediatric prescribing
Most psychotropic drugs used in adults are not licensed for use in children or
­adolescents.4 The Medicines Act 1968 and European legislation make provision for
doctors to use medicines in an off-­label or out-­of-­licence capacity or to use unlicensed medicines. Where possible a licensed preparation should be prescribed
(Table 5.1), however it is recognised that the informed use of unlicensed medicines,
or of licensed medicines in an ‘off-­label’ way, is often necessary in paediatric
­practice. Individual prescribers are always responsible for ensuring that there is
adequate information to support the quality, efficacy, safety and intended use of a
drug before prescribing it.5
When writing a prescription in most countries, inclusion of age is a legal requirement in the case of prescription-­only medicines for children under 12 years of age,
but it is preferable to state the age for all prescriptions for children.
Prescribing in children and adolescents
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Table 5.1  Psychotropic medications approved by the UK Medicines and Healthcare products Regulatory Agency
(MHRA), European Medicines Agency and the US Food and Drug Administration for children and adolescents
(January 2024).­6–­9
Condition
UK MHRA
approval only;
age (years)
European Medicine
Agency;* age (years)
US Food and Drug
Administration;
age (years)
ADHD
­Amfetamine–­dexamfetamine
mixed salts
–­
–­
3+
­Amfetamine–­dexamfetamine
mixed salts extended release
–­
–­
6+
Atomoxetine
6+
6+
6+
Clonidine extended release
–­
–­
­6–­17
Dexamfetamine
­6–­17
­6–­17
­3–­16
Dexamfetamine sustained release
–­
–­
­6–­16
Dexmethylphenidate
–­
–­
6+
Guanfacine extended release
­6–­17
­6–­17
­6–­17
Lisdexamfetamine
6+
6+
­6–­17
Methamfetamine
–­
–­
­6–­17
Methylphenidate
6+
6–18
6+
Viloxazine
–­
–­
6+
Anxiety disorders
Duloxetine
–­
–­
GAD 7+
Escitalopram
–­
–­
GAD 7+
Autism spectrum disorder
(irritability)
Aripiprazole
–­
–­
­6–­17
Risperidone
–­
–­
­5–­17
Bipolar disorder (depressive
episodes)
Lurasidone
–­
–­
10+
­Olanzapine–­fluoxetine combination
–­
–­
10+
Bipolar disorder (manic or
mixed episodes)
Aripiprazole
Manic episodes 13+
Manic episodes 13+
Manic or mixed episodes 10+
Asenapine
–­
–­
10+
Lithium
–­
–­
7+
Lithium extended release
–
–
12+
Olanzapine
–­
–­
13+
Quetiapine extended release
–­
–­
10+
(Continued )
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Condition
UK MHRA
approval only;
age (years)
European Medicine
Agency;* age (years)
US Food and Drug
Administration;
age (years)
Risperidone
–­
–­
10+
Ziprasidone
–­
10+
–­
Conduct disorder
Risperidone
­5–­18
­5–­18
–­
Depressive disorder
Amitriptyline
–­
–­
12+
Escitalopram
–­
–­
12+
Fluoxetine
8+
8+
8+
Enuresis
Amitriptyline
­6–­17
­6–­17
–­
Imipramine
­6–­17
­5–­18
­6–­17
Insomnia (in autism spectrum disorder or Smith Magenis syndrome)
Melatonin extended release
­6–­17
­2–­18
–­
Insomnia (in ADHD)
Melatonin immediate release
­6–­17
–­
–­
Insomnia (short term)
Promethazine
5+
–­
–­
Obsessive compulsive disorder
Clomipramine
–­
–­
10+
Fluoxetine
–­
–­
7+
Fluvoxamine
8+
8+
8+
Sertraline
6+
6+
6+
Schizophrenia
Aripiprazole
15+
15+
13+
Brexpiprazole
–­
–­
13+
Lurasidone
13+
–­
13+
Olanzapine
–­
–­
13+
Paliperidone
15+
15+
12+
Quetiapine
–
–­
13+
Risperidone
–­
–­
13+
Sulpiride
14+
6+
–­
Tourette’s disorder
Aripiprazole
–­
–­
­6–­18
*Approvals may differ in individual countries.
GAD, generalised anxiety disorder.
Table 5.1  (Continued)

02 - References
References
Prescribing in children and adolescents
CHAPTER 5
References
Gerlach M, et al. Psychiatric Drugs in Children and Adolescents. Basic Pharmacology and Practical Applications. Vienna: Springer-­Verlag;
Turner M, et al. Prescribing Medicines for Children: From drug development to practical administration. London: Pharmaceutical Press. Royal
Pharmaceutical Society; 2019.
Paediatric Formulary Committee. BNF for Children (online). London: BMJ, Pharmaceutical Press, and RCPCH Publications; http://www.
medicinescomplete.com.
Smogur M, et al. Psychotropic drug prescription in children and adolescents: approved medications in European countries and the United
States. J Child Adolesc Psychopharmacol 2022; 32:­80–­88.
Sharma AN, et al. BAP position statement: off-­label prescribing of psychotropic medication to children and adolescents. J Psychopharmacol
2016; 30:­416–­421.
Cortese S, et al. Psychopharmacology in children and adolescents: unmet needs and opportunities. Lancet Psychiatry 2023; 11:­143–­154.
EMC. Summaries of Product Characteristics. 2024; https://www.medicines.org.uk/emc/.
IBM Watson Health. IBM Micromedex Solutions. 2024; https://www.ibm.com/watson-­health/about/micromedex.
Gelbe Liste Pharmindex. Gelbe Liste Online. News, Infos und Datenbanken für Ärzte, Apotheker und Fachpersonal aus Medizin und
Pharmazie. 2024; https://www.gelbe-­liste.de/.

03 - Depression in children and adolescents
Depression in children and adolescents

04 - Diagnostic issues
Diagnostic issues

05 - Clinical guidance
Clinical guidance
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CHAPTER 5
Depression in children and adolescents
Diagnostic issues
Approximately 15% of young people experience depression by age 18 years and these
young people often have significant functional impairment and risk of harm.1 Compared
with depressed adults, young people with depression tend to experience more irritability, loss of energy, insomnia and weight change, and less anhedonia and concentration
problems.2 These symptoms can overlap with and appear similar to other disorders or
can be minimised and incorrectly attributed to typical teenage development, making
diagnosis challenging. Assessments should therefore be undertaken by clinicians who
understand developmental variations and can accurately identify depression in young
people.3
Clinical guidance
For mild depression in children and adolescents, the UK National Institute for Health
and Care Excellence (NICE) guidelines4 and American Academy of Child and Adolescent
Psychiatry (AACAP) practice parameter3 recommend that supportive care or psychological intervention should be considered as first-­line treatment, and that antidepressant medication should not be prescribed.
For moderate to severe depression in young people, these same guidelines recommend offering psychological therapy, either alone or in combination with antidepressant medication. In addition, the AACAP practice parameter recommends that
antidepressant medication alone could be considered, particularly if the presentation is
severe and the patient is unable to engage in talking therapy, if psychological interventions are not available or if this is the patient’s and family’s preference.
These guidelines were informed by research evidence for the effectiveness of selective
serotonin reuptake inhibitors (SSRIs) in treating depression in young people. For example, a seminal large UK National Institute of Mental Health (NIMH) funded randomised
controlled trial (RCT) –­ the Treatment of Adolescents With Depression Study (TADS)­5­­ –
found a fluoxetine response rate of 61% over the acute (12-­week) phase, which was
significantly higher than the placebo response rate of 35%, giving a number needed to
treat (NNT) of 4.5 Subsequent systematic reviews and meta-­analyses, which include this
trial and others, have provided further evidence demonstrating that SSRIs are effective at
improving symptoms and functioning, and are largely acceptable treatments for depression in young people. However, several individual studies and systematic reviews studies
report less certain ­effects­­6–10 and a 2021 Cochrane review described antidepressant effects
as ‘small and unimportant’.11
The current evidence base is unclear about whether SSRI medications alone, psychological therapy alone or combined treatment is most effective for treating depression in
children and adolescents. TADS found that fluoxetine alone or in combination with
cognitive behavioural therapy (CBT) might accelerate treatment response, and that
adding CBT might decrease adverse effects including suicidality, so enhancing the safety
of fluoxetine.5,12 However, other studies have not replicated this finding,13,14 including
the Adolescent Depression Antidepressants and Psychotherapy Trial (ADAPT), which
found no benefit in combining fluoxetine with CBT over fluoxetine alone.15 A network

06 - Prescribing for depression in children and ad
Prescribing for depression in children and adolescents
Prescribing in children and adolescents
CHAPTER 5
meta-­analysis comparing several treatments for depression in children and adolescents
also found that combined fluoxetine and CBT was no more effective than fluoxetine
alone but found that this combination was more effective than CBT alone.16
Prescribing for depression in children and adolescents
Before prescribing
■
■Undertake a comprehensive assessment: Establish a clinical diagnosis of depression.
Exclude differential diagnoses, including psychiatric disorders (such as bipolar affective disorder), medical disorders (such as endocrine disorders) and medication-­related
effects (such as steroid adverse effects). Identify any comorbid psychiatric or medical
conditions. Consider contraindications to SSRIs and potential interactions. Assess
risk of harm to self and others. Formulate considering factors that could predispose,
precipitate and perpetuate depression, such as family history of psychiatric disorders
(including depression and bipolar affective disorder) and environmental stressors
(including victimisation and other adverse experiences). If any co-­occurring problems
are identified, these should be addressed and prioritised based on a comprehensive
formulation.
■
■Measure baseline severity: Measures of depression symptoms include the clinician-­
administered Children’s Depression Rating Scale-­Revised (CDRS-­R)17,18 and the childand parent-­reported Mood and Feelings Questionnaire (MFQ)19 or Revised Children’s
Anxiety and Depression Scale (RCADS).20 Measures of functional impairment include
the Children’s Global Assessment Scale (CGAS).21
■
■Obtain informed consent: Discuss the nature, course and treatment of depression,
potential adverse effects of medication, delay in onset of treatment effects, plan for
monitoring and maintenance of medication and potential discontinuation effects.
■
■Develop a safety plan: In all but exceptional circumstances, a parent or carer should
be responsible for the secure storage of medication for a child or adolescent. Advise
the young person and their parent/carer of professionals or services they should
contact if they experience significant adverse effects, risk of harm or worsening
symptoms.
What to prescribe
■
■Fluoxetine is the recommended first-­line medication for depression in children and
adolescents.3,4 It has the strongest current evidence for efficacy,6,9,11,16,22,23 showing
moderate effects in reducing depression symptoms versus placebo (standardised mean
difference = 0.51).16 In the UK, NICE states that fluoxetine is the only antidepressant
for which clinical trial evidence shows that benefits outweigh risks.4 Fluoxetine
should be started at a dose of 10mg daily which can be increased after 1 week to the
minimum therapeutic dose of 20mg daily. Higher doses (up to ­40–­60mg daily) may
be considered, particularly in older children of higher body weight or when, in severe
illness, an early clinical response is considered a priority.4,5,15,24 The long half-­life of
fluoxetine may be beneficial for adolescents because it confers a reduced risk of discontinuation effects or relapse if doses are delayed or missed.25 Fluoxetine is approved
for treatment of depression in patients aged 8 years and over by the US Food and
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Drug Administration (FDA), and by the European Medicines Agency and the UK
Medicines and Healthcare products Regulatory Agency (MHRA) if the young person
has moderate to severe depression and has not responded to psychological
therapy.26
■
■Sertraline and escitalopram have also been found to be more effective than placebo
for treating depression in young people6,22 and should be considered as alternatives if
fluoxetine is not tolerated. Sertraline and escitalopram should also be started at low
doses (­25–­50mg daily and ­5–­10mg daily, respectively) and titrated to therapeutic
doses (­50–­200mg daily and ­10–­20mg daily, respectively). The half-­lives of sertraline,
escitalopram and some other antidepressants may be shorter in young people than
adults, so twice daily dosing could be considered to prevent discontinuation symptoms.27 Escitalopram is approved by the FDA for treatment of depression in patients
aged 12 years and over.
■
■Duloxetine and venlafaxine may be effective but are relatively poorly tolerated.28
■
■Agomelatine was more effective than placebo in children aged ­7–­11 years and showed
similar efficacy to fluoxetine. A dose of 10mg seems to be effective. Agomelatine is
extremely well tolerated but not licensed for children or adolescents. Liver function
test (LFT) changes occurred in 1% of participants.29 Vortioxetine was no more effective than placebo in a large study of ­12–­17-­year-­old children.30
■
■For children and adolescents who have significant depressive symptoms resulting in
distress or impairment despite an adequate trial of an SSRI alone, consider combination SSRI and psychological therapy. There is some limited evidence that combination
treatment may be more beneficial than SSRI alone for some young people.6,­31–­33
■
■For children and adolescents who have significant depressive symptoms resulting in
distress or impairment despite adequate trials of an SSRI (fluoxetine) and psychological therapy, consider a switch to a different SSRI (sertraline, escitalopram).4,31 This
guidance is largely based on the Treatment of Resistant Depression in Adolescents
(TORDIA) trial,24 the only RCT that has examined the comparative efficacy of different treatment strategies for SSRI-­resistant depression in young people.24 This trial
found that many participants improved when switched to another SSRI or venlafaxine (response rate 47% and 48%, respectively) and improved even more when this
medication switch was combined with starting concurrent CBT (response rate 55%
vs 41% without CBT) after 12 weeks of treatment. A switch to an SSRI was just as
efficacious as a switch to venlafaxine but had less frequent and severe side effects, so
an SSRI switch is preferred.
■
■If limited response despite adequate trials of these medications and psychological
therapy, consider augmenting SSRI treatment with another medication such as a
second-­generation antipsychotic or lithium. (Also consider augmentation if there has
been partial response to an SSRI.31) Alternatively, consider switching to an antidepressant from a different class, for example ­mirtazapine34 –­ especially if poor sleep is
a problem. There are no RCTs testing the effectiveness of these strategies in children
or adolescents, and so this guidance is largely based on evidence from studies of
adults with treatment-­resistant depression, in addition to very limited follow-up of
TORDIA participants receiving open-­label treatment.31,35
■
■Finally, if still no response to these medications and the young person’s depression is
very severe, ketamine, repetitive transcranial magnetic stimulation (rTMS) or electroconvulsive therapy can be considered. These interventions have an evidence base and

07 - After prescribing
After prescribing
Prescribing in children and adolescents
CHAPTER 5
are approved for use in adults with treatment-­resistant depression, but there is no
substantial evidence in children and adolescents.31 With regard to ketamine, or its
enantiomer esketamine, emerging evidence suggests that it may be effective and adequately tolerated in adolescents with treatment-­resistant depression based on a small
number of studies, including two small RCTs.­36–­38 Considering rTMS, initial evidence
suggested that it may be effective, again based on a small number of studies and a
small RCT, but a larger RCT found no evidence of effectiveness.39 Electroconvulsive
therapy (ECT) has limited evidence of effectiveness in young people, although one
randomised trial in adolescents showed good effect against both depression and suicide.40 Therefore, these treatments’ unknown potential effects on the developing brain
need to be considered carefully and weighed up against the risks of not attempting
these treatments.41 Further research is greatly needed to inform clinical decisions.42
■
■NICE warns against prescribing paroxetine, venlafaxine, tricyclic antidepressants or
St John’s wort for depression in young people, because of potential adverse effects
and interactions.4
Table 5.2 summarises medication treatment for depression in children and adolescents.
After prescribing
Acute phase
■
■Monitor for adverse effects regularly, for example weekly for the first 4  weeks.
Children and adolescents generally tolerate SSRIs well. Potential adverse effects
include those experienced by adults, described in Chapter 3. Additionally, young people taking SSRIs have a small increased risk of suicidality and switch to mania, as well
as activation effects (see ‘Specific issues’ later in this chapter). Therefore, risk of harm,
mood and behaviour should be monitored closely and addressed.3,4,6,31
■
■After 4  weeks of SSRI treatment at a therapeutic dose, assess response including
depression severity using the measures completed at baseline. Most therapeutic effects
appear by 4 weeks.43
■
■If partial or non-­response, consider the possibility of poor treatment adherence, inaccurate diagnosis, comorbidity or modifiable maintaining factors.
Table 5.2  Summary of pharmacotherapy for depression in children and adolescents.3,4,6,31
Medication
Starting dose
Therapeutic dose range
First line
Fluoxetine
10mg/day
­20–­60mg/day
Second line
Sertraline
Escitalopram
Citalopram*
­25–­50mg/day
­5–­10mg/day
10mg/day
­50–­200mg/day
­10–­20mg/day
­20–­40mg/day
Subsequently
Consider augmentation of antidepressant with second-­generation antipsychotic
or lithium.†
Consider switching to an antidepressant from a different class, such as mirtazapine.
*Caution advised in cardiac or hepatic disease.
†No randomised controlled trials available in young people (but there is evidence from adult trials).

08 - Specific issues
Specific issues
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■
■If none of these factors explains the continued depressive symptoms and the young
person does not have adverse effects, consider increasing the dose. Reassess every
4 weeks.3,31 This recommendation is largely based on evidence from adult depression
trials, which have demonstrated small but significant improvements in depression
symptoms with higher doses of SSRIs,44 as there has been only limited research on
this topic in children and adolescents.45
■
■If adverse effects develop, consider reducing the dose to the highest tolerated dose.
■
■If partial or non-­response after 8 weeks of the maximum recommended (or highest
tolerated) therapeutic dose of an SSRI, consider the medication changes outlined
earlier.31
Maintenance phase
Continue medication for ­6–­12 months after remission to reduce the risk of relapse.
Consider a longer maintenance phase if depressive episodes were recurrent or
chronic.3,4,6,31 Again, this recommendation is largely based on evidence from adult
depression trials, in addition to very limited research in children and adolescents.46,47
Discontinuation phase
Discontinuation may be considered after the maintenance phase. This is best
­undertaken during a period of low stress. Taper medications slowly and hyperbolically
(see Chapter 3) to minimise the risk of discontinuation symptoms.3,4,6,31
Specific issues
■
■Age
The evidence base for these recommendations is stronger for adolescents than for
children, so caution should be higher when considering prescribing for children.
There has been no research investigating antidepressant medication use in pre-­school
children, and medications are not recommended for this age group.4,22
■
■Suicidality
Antidepressant medication has been linked to an increased risk of suicidality in young
people, which led to warnings issued by the US FDA, the European Medicines Agency
and the UK MHRA in ­2003–­2005. Subsequent meta-­analyses have also found evidence of this association with reported suicidality,11,22,48 particularly for venlafaxine,16,23
as well as a link with aggression.49 A meta-­analysis of reported suicidal thoughts or
attempts in depression trials found a pooled absolute rate in antidepressant-­treated
young people of 3% and in those receiving placebo of 2%, giving a number needed to
harm (NNH) of 112 (note these rates are low, probably because those with high risk
of suicidality were often excluded from trials).50 Concern has also been expressed
about emergent suicidality with escitalopram.51 To date, there has been no link between
antidepressant use and completed suicides, but extreme care should be exercised.
Untreated depression is a significant risk factor for suicidality. After the FDA warning on antidepressant use in children and adolescents, antidepressant use declined,
untreated depression increased and suicide rates increased.52,53 Given the risks of
untreated depression, including completed suicide and impaired functioning, and that
many more patients benefit from SSRIs than those who experience these serious adverse
events, it is thought that the benefits of antidepressants, particularly fluoxetine, are

09 - References
References
Prescribing in children and adolescents
CHAPTER 5
likely to outweigh these risks in moderate to severe depression. Nonetheless, it bears
repeating that the risk of suicide should be very carefully monitored.3,4,6,31
■
■Activation and manic switch
Activation adverse effects of antidepressant ­medication –­ including increased activity,
restlessness and ­agitation –­ occur more commonly in children than in adolescents or
adults. These effects, including mild symptoms, may occur in about 10% of children
with depression taking SSRIs.54,55 They are usually a transient response to starting
medication or increasing dose and should be differentiated from manic switch.
Conversion to mania is rarer but is observed more often in young people taking antidepressants than in adults.56,57 However, there is no clear evidence that this switch is
caused by antidepressants.
References
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Acad Child Adolesc Psychiatry 2015; 54:­37–­44.e32.
Rice F, et al. Adolescent and adult differences in major depression symptom profiles. J Affect Disord 2019; 243:­175–­181.
Birmaher B, et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child
Adolesc Psychiatry 2007; 46:­1503–­1526.
National Institute for Health and Care Excellence (NICE). Depression in children and young people: identification and management. NICE
Guideline [NG134]. 2019 (last checked December 2023). www.nice.org.uk/guidance/ng134.
March J, et al. Fluoxetine, cognitive-­behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents
with Depression Study (TADS) randomized controlled trial. JAMA 2004; 292:­807–­820.
Goodyer IM, et  al. Practitioner Review: Therapeutics of unipolar major depressions in adolescents. J Child Psychol Psychiatry 2019;
60:­232–­243.
Locher C, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-­norepinephrine reuptake inhibitors, and placebo for
common psychiatric disorders among children and adolescents: a systematic review and meta-­analysis. JAMA Psychiatry 2017;
74:­1011–­1020.
Teng T, et al. Effect of antidepressants on functioning and quality of life outcomes in children and adolescents with major depressive disorder:
a systematic review and meta-­analysis. Transl Psychiatry 2022; 12:183.
Vitiello B, et al. Pharmacological treatment of children and adolescents with depression. Expert Opin Pharmacother 2016; 17:­2273–­2279.
Walkup JT. Antidepressant efficacy for depression in children and adolescents: industry-­ and NIMH-­funded studies. Am J Psychiatry 2017;
174:­430–­437.
Hetrick SE, et al. New generation antidepressants for depression in children and adolescents: a network meta-­analysis. Cochrane Database
Syst Rev 2021; 5:CD013674.
Treatment for Adolescents With Depression Study (TADS) Team. The Treatment for Adolescents With Depression Study (TADS): long-­term
effectiveness and safety outcomes. Arch Gen Psychiatry 2007; 64:­1132–­1143.
Cox GR, et al. Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents.
Cochrane Database Syst Rev 2014; 11:CD008324.
Dubicka B, et al. Combined treatment with cognitive-­behavioural therapy in adolescent depression: meta-­analysis. Br J Psychiatry 2010;
197:­433–­440.
Goodyer I, et al. Selective serotonin reuptake inhibitors (SSRIs) and routine specialist care with and without cognitive behaviour therapy in
adolescents with major depression: randomised controlled trial. BMJ 2007; 335:142.
Zhou X, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of
children and adolescents with depressive disorder: a systematic review and network meta-­analysis. Lancet Psychiatry 2020; 7:­581–­601.
Poznanski EO, et al. Children’s Depression Rating Scale, Revised (CDRS-­R). Los Angeles: Western Psychological Services; 1996.
Mayes TL, et al. Psychometric properties of the Children’s Depression Rating Scale-­Revised in adolescents. J Child Adolesc Psychopharmacol
2010; 20:­513–­516.
Angold A, et al. Development of a short questionnaire for use in epidemiological studies of depression in children and adolescents. Int J
Methods Psychiatr Res 1995; 5:­237–­249.
Chorpita BF, et al. Assessment of symptoms of DSM-­IV anxiety and depression in children: a revised child anxiety and depression scale.
Behav Res Ther 2000; 38:­835–­855.
Shaffer D, et al. A children’s global assessment scale (CGAS). Arch Gen Psychiatry 1983; 40:­1228–­1231.
Hetrick SE, et al. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev 2012;
11:CD004851.
Cipriani A, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-­analysis. Lancet 2016; 388:­881–­890.
Brent D, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-­resistant
depression: the TORDIA Randomized Controlled Trial. JAMA 2008; 299:­901–­913.
Wilens TE, et al. Fluoxetine pharmacokinetics in pediatric patients. J Clin Psychopharmacol 2002; 22:­568–­575.
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26. Aurobindo ­Pharma –­ Milpharm Ltd. Summary of product characteristics. Fluoxetine 20mg capsules. 2020 (last checked December 2023);
https://www.medicines.org.uk/emc/product/11909/smpc#gref.
27. Findling RL, et  al. The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression. J Child Adolesc
Psychopharmacol 2006; 16:­131–­145.
28. Rao Y, et al. Efficacy and tolerability of antidepressant drugs in treatment of depression in children and adolescents: a network meta-­analysis.
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022; 51:­480–­490.
29. Arango C, et al. Safety and efficacy of agomelatine in children and adolescents with major depressive disorder receiving psychosocial counselling:
a double-­blind, randomised, controlled, phase 3 trial in nine countries. Lancet Psychiatry 2022; 9:­113–­124.
30. Findling RL, et al. Vortioxetine for major depressive disorder in adolescents: 12-­week randomized, placebo-­controlled, fluoxetine-­referenced,
fixed-­dose study. J Am Acad Child Adolesc Psychiatry 2022; 61:­1106–­1118.e1102.
31. Dwyer JB, et al. Annual research review: defining and treating pediatric treatment-­resistant depression. J Child Psychol Psychiatry 2020;
61:­312–­332.
32. Asarnow JR, et al. Treatment of selective serotonin reuptake inhibitor-­resistant depression in adolescents: predictors and moderators of treatment response. J Am Acad Child Adolesc Psychiatry 2009; 48:­330–­339.
33. Curry J, et al. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child
Adolesc Psychiatry 2006; 45:­1427–­1439.
34. Haapasalo-­Pesu KM, et al. Mirtazapine in the treatment of adolescents with major depression: an open-­label, multicenter pilot study. J Child
Adolesc Psychopharmacol 2004; 14:­175–­184.
35. Emslie GJ, et al. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry 2010; 167:­782–­791.
36. Dwyer JB, et al. Efficacy of intravenous ketamine in adolescent treatment-­resistant depression: a randomized midazolam-­controlled trial.
Am J Psychiatry 2021; 178:­352–­362.
37. Di Vincenzo JD, et al. The effectiveness, safety and tolerability of ketamine for depression in adolescents and older adults: a systematic review.
J Psychiatr Res 2021; 137:­232–­241.
38. Zhou Y, et al. Effect of repeated intravenous esketamine on adolescents with major depressive disorder and suicidal ideation: a randomized
active-­placebo-­controlled trial. J Am Acad Child Adolesc Psychiatry 2024; 63:507–518.
39. Sigrist C, et al. Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-­analysis of aggregated and individual-­patient data from uncontrolled studies. Eur Child Adolesc Psychiatry 2022; 31:­1501–­1525.
40. Cai H, et  al. Suicidal ideation and electroconvulsive therapy: outcomes in adolescents with major depressive disorder. J ECT 2023;
39:­166–­172.
41. Zimmermann KS, et al. Esketamine as a treatment for paediatric depression: questions of safety and efficacy. Lancet Psychiatry 2020;
7:­827–­829.
42. Ayvaci ER, et  al. Special populations: treatment-­resistant depression in children and adolescents. Psychiatr Clin North Am 2023;
46:­359–­370.
43. Varigonda AL, et al. Systematic review and meta-­analysis: early treatment responses of selective serotonin reuptake inhibitors in pediatric
major depressive disorder. J Am Acad Child Adolesc Psychiatry 2015; 54:­557–­564.
44. Jakubovski E, et al. Systematic review and meta-­analysis: dose-­response relationship of selective serotonin reuptake inhibitors in major
depressive disorder. Am J Psychiatry 2016; 173:­174–­183.
45. Heiligenstein JH, et al. Fluoxetine 40-­60 mg versus fluoxetine 20 mg in the treatment of children and adolescents with a less-­than-­complete
response to nine-­week treatment with fluoxetine 10-­20 mg: a pilot study. J Child Adolesc Psychopharmacol 2006; 16:­207–­217.
46. Emslie GJ, et al. Fluoxetine treatment for prevention of relapse of depression in children and adolescents: a double-­blind, placebo-­controlled
study. J Am Acad Child Adolesc Psychiatry 2004; 43:­1397–­1405.
47. Emslie GJ, et al. Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents. Am J Psychiatry 2008;
165:­459–­467.
48. Li K, et al. Risk of suicidal behaviors and antidepressant exposure among children and adolescents: a meta-­analysis of observational studies.
Front Psychiatry 2022; 13:880496.
49. Sharma T, et al. Suicidality and aggression during antidepressant treatment: systematic review and meta-­analyses based on clinical study
reports. BMJ 2016; 352:i65.
50. Bridge JA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-­
analysis of randomized controlled trials. JAMA 2007; 297:­1683–­1696.
51. Plöderl M, et al. Re: “A multicenter double-­blind, placebo-­controlled trial of escitalopram in children and adolescents with generalized anxiety disorder” by Strawn et al. –­ Concerning harm-­benefit ratio in a recent trial about escitalopram for generalized anxiety disorder. J Child
Adolesc Psychopharmacol 2023; 33:­295–­296.
52. Gibbons RD, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007; 164:­1356–­1363.
53. Libby AM, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007;
164:­884–­891.
54. Offidani E, et al. Excessive mood elevation and behavioral activation with antidepressant treatment of juvenile depressive and anxiety disorders: a systematic review. Psychother Psychosom 2013; 82:­132–­141.
55. Safer DJ, et al. Treatment-­emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents. J
Child Adolesc Psychopharmacol 2006; 16:­159–­169.
56. Baldessarini RJ, et al. Antidepressant-­associated mood-­switching and transition from unipolar major depression to bipolar disorder: a review.
J Affect Disord 2013; 148:­129–­135.
57. Virtanen S, et al. Antidepressant use and risk of manic episodes in children and adolescents with unipolar depression. JAMA Psychiatry 2024;
81:­25–­33.

10 - Bipolar disorder in children and adolescents
Bipolar disorder in children and adolescents

11 - Clinical guidance
Clinical guidance
Prescribing in children and adolescents
CHAPTER 5
Bipolar disorder in children and adolescents
Clinical guidance
Before prescribing
■
■Establish clinical diagnosis informed by structured instrument assessment if possible.
Symptom checklists should be avoided, especially in primary care. Try to monitor
symptom patterns prospectively with mood or sleep diaries. If in doubt, seek specialist advice early on.
■
■Explain the diagnosis to the patient and family and invest time and effort in psycho­
education. This is likely to improve adherence and help children and adolescents
and their families appreciate early warning signs of a relapse. Furthermore, there is
evidence that such approaches reduce relapse rates, at least in adults.1
■
■Measure baseline symptoms of mania (e.g. Young Mania Rating Scale2 [YMRS] and
the parent YMRS3), depression (e.g. Children’s Depression Rating Scale4 [CDRS])
and impairment (e.g. Clinical Global ­Impression –­ BD version5). Use these to set clear
and realistic treatment goals.
■
■Measure baseline height, weight, waist and hip circumference, pulse, blood pressure
and electrocardiogram (ECG) and obtain baseline bloods as appropriate (fasting blood
glucose, HbA1c, fasting lipid profile, full blood count [FBC], urea and electrolytes
[U&E], creatine kinase, LFTs, prolactin and thyroid function).
What to prescribe
■
■Tables 5.3, 5.4, 5.5 and 5.6 summarise medication use in bipolar mania and depression and acute mania.
■
■For the treatment of mania and hypomania in children and adolescents, UK NICE
guidelines suggest following the same recommendations as for ­adults  –­ second-­
generation antipsychotics (SGAs) may be used as first-­line treatment, and mood stabilisers (MS) can be added after a failure of two trials of SGAs.6 The difference in
comparison with adult guidelines is that NICE recommends that SGAs should not be
routinely offered for more than 12 weeks. This information should be shared with the
child or adolescent and their family.
■
■SGAs seem to show greater short-­term efficacy (effect size [ES] = 0.65 compared with
placebo) than MS (ES = 0.20 compared with placebo) in youth, according to a
2010 meta-­analysis.7
■
■SGAs produce significantly greater weight gain (particularly olanzapine) and
­somnolence in children and adolescents compared with adults,7 although weight gain
assessment is made complicated by normal growth at this time of life.
■
■Valproate should be completely avoided in all adolescents.
■
■Adherence to lithium cannot be assumed and blood level testing may be difficult in
adolescents.
■
■Overall, we recommend the use of SGAs as first line for the acute treatment of mania
in children and adolescents (Tables 5.3 and 5.5).
■
■It is helpful to document family history of response and non-­response to pharmacological treatment as there is evidence to suggest that pharmacological response, at
least for lithium, runs in families.8

12 - Other treatments
Other treatments
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CHAPTER 5
After prescribing
■
■Assess and measure symptoms on a regular basis to establish effectiveness.
■
■Monitor weight, height and waist to hip circumference at each visit and repeat all
fasting bloods at 3 months (then every 6 months). Offer advice on healthy lifestyle
and exercise.
■
■The duration of most medication trials is ­3–­5 ­weeks –­ this is the period over which most
improvement is anticipated to occur. This should guide decisions about how long to try
a single drug in a patient. A complete absence of response at 2 weeks should prompt
consideration of a switch to another SGA (or a dose increase where labelling allows).
■
■If there is no response, check adherence, measure blood levels where possible and
consider increasing the dose. Consider concurrent use of an SGA and MS.
■
■Judicious extrapolation of the evidence from adults9 is required because of the very
limited evidence base in youths with bipolar disorder. This includes treatment duration and prophylaxis.6,7,10 Maintenance treatment should follow adult guidelines.
Consider the use of lithium early in the course of treatment, either by switching to
lithium monotherapy prophylaxis or as an adjunct to a successful acute medication.
Lithium has therapeutic advantages over other options in adults but should only be
used where adherence is assured.
Specific issues
■
■Bipolar depression is a common clinical challenge and its treatment has been studied
much less in youths than in adults (Tables 5.4 and 5.6). Antidepressants should be
used rarely and with care for the minimum duration possible and only in the ­presence
of an antimanic agent.6 There is limited evidence for the benefit of antidepressants in
bipolar depression in adults.11 Because of the dearth of trials in youth, we are compelled to extrapolate from adult studies,6 which suggest use of the ­olanzapine/fluoxetine combination as the most effective treatment, along with lurasidone, which is
supported by evidence from several trials in children aged ­10–­17 years.­12–­14 The metabolic effects of olanzapine arguably make it a second-­line choice after lurasidone.
■
■The exact relationship between ADHD and bipolar depression is still debated. Some
evidence suggests that stimulants in children with ADHD and manic symptoms may
be well tolerated15 and that they may be safe and effective to use after mood stabilisation.15 Caution and experience with prescribing these drugs are required.
■
■The DSM-­5 category of disruptive mood dysregulation disorder (DMDD) includes
severely irritable children (who were commonly misdiagnosed as having bipolar
depression in the USA). There is no established treatment for DMDD. Lithium is
­ineffective16 but SSRIs and psychological treatment options, such as parenting
­interventions, may be considered.17
Other treatments
■
■Adjunct treatments including psychoeducation, CBT and especially family-­focused
interventions can enhance treatment and reduce depression relapse rates in bipolar
disorder.18
Prescribing in children and adolescents
CHAPTER 5
■
■There is emerging evidence that a combination of omega-­3 fatty acids with inositol is
effective in mania and hypomania in children aged ­5–­12 years.19 Confirmatory trials
are needed.
■
■Cariprazine may be effective in young people but evidence is limited.20
■
■The use of high-­frequency rTMS in adolescents with treatment-­resistant unipolar
depression is only supported by open-­label studies21 and no RCT has been done
in youth with either unipolar or bipolar depression. Therefore, its use is
still  ­considered experimental. One randomised sham-­controlled study found
rTMS ineffective in treating acute mania in youth (as an add-­on to standard
pharmacotherapy).22
■
■One small trial supported the adjunctive use of melatonin (6mg/day) in adults with
mania.23 Evidence is not yet sufficient to recommend its use in children.
Table 5.3  Pharmacological treatments of mania in children and adolescents.
Medication
Comment
Lithium
Lithium is cleared relatively quickly in children so twice daily dosing will be required, especially
when using liquid or non-­modified-release preparations.24 One double-­blind placebo-­controlled
randomised trial25 showed significant reductions in substance use and clinical ratings after 6 weeks
in adolescents with bipolar disorder and comorbid substance misuse. In a double-­blind placebo-­
controlled discontinuation trial (N = 40) over 2 weeks, no significant difference in relapse rates
were found between lithium and placebo.26
A later double-­blind placebo-­controlled study (N = 81), over 8 weeks, demonstrated a
significantly larger change in YMRS score in lithium-­treated youths. There was a significant
increase in thyrotropin with lithium, but no difference in weight gain.27
Lithium and divalproex did not differ in an 18-­month maintenance trial in youths (N = 60) who
initially stabilised on combination pharmacotherapy of lithium and divalproex.28 However,
given the compelling evidence for lithium maintenance and prophylaxis in adults, we
recommend that clinicians consider its use in adolescents in preference to valproate. Valproate
should be avoided in adolescents in any case.
A meta-­analysis29 found lithium to be ‘clearly inferior’ to risperidone in mania. Lithium may
also be inferior to quetiapine in the treatment of mania in children and adolescents.30
One small 6-­month study found higher relapse rates in those who discontinued lithium
compared with those who continued.31 Another naturalistic 8-­month study showed lithium to
be effective and well tolerated.32
Valproate
In an RCT (N = 150)33 divalproex ER (titrated to clinical response or ­80–­125mg/L) did not lead
to significant differences in mean YMRS compared with placebo at 4 weeks. (Also see
risperidone and quetiapine sections below.) Valproate should be avoided in all peri-­ and
post-­pubertal children and adolescents.
Oxcarbazepine
A double-­blind placebo-­controlled study (N = 116) did not show significant differences
between placebo and oxcarbazepine (mean dose 1515mg/day) in reducing mania rating at
7 weeks.34
(Continued )
576
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CHAPTER 5
Medication
Comment
Olanzapine
A double-blind placebo-­controlled study (N = 161)35 showed olanzapine (­5–­20mg/day) to be
significantly more effective than placebo over a period of 3 weeks. There was greater weight
gain in the treatment group (weight gain was 3.7kg for olanzapine vs 0.3kg for placebo) and
associated significantly increased fasting glucose, total cholesterol, AST, ALT and uric acid. The
addition of topiramate reduces weight gain by more than a half.36
Risperidone
A double-­blind placebo-­controlled study (N = 169) showed risperidone (at doses 0.­5–­2.5 or
­3–­6mg) to be more effective than placebo in YMRS mean score reduction in a 3-­week
follow-up.37 The lower dose led to the same benefits at a lower risk of adverse effects.
Sleepiness and fatigue were common. Mean weight increase in treatment groups was 0.7kg
vs 1.7kg for the low-­dose arm and 1.4kg for the high-­dose arm.
In the Treatment of Early Age Mania (TEAM) study, higher response rates (and metabolic
side effects) occurred with risperidone (mean dose 2.57mg) than with lithium (mean level
1.09mmol/L) and divalproex sodium (mean level 113.6mg/L).38 A randomised follow-up of
this study showed again the superiority of risperidone as an alternative treatment for
non-­responders to lithium and divalproex sodium, and as an add-­on treatment to partial
responders to the two drugs.39 These results need to be interpreted with caution as the
definition of mania was broader than that used in some countries. The same caveat applies
when considering another double-­blind placebo-­controlled trial showing significantly better
results for risperidone (mean dose 0.5mg) than for valproic acid (mean level 81mg/L) in
­3–­7-­year-­old children supposedly diagnosed with mania.40
Quetiapine
A double-­blind placebo-­controlled study (N = 277)41 showed quetiapine (at doses of 400 or
600mg/day) to be significantly better than placebo in reducing mean YMRS scores at 3 weeks.
The most common side effects included somnolence and sedation. Weight gain was 1.7kg in
the quetiapine group and 0.4kg for placebo.
Quetiapine is effective as an adjunct to valproate compared with valproate alone (N = 30,
6 weeks)42 and was as effective as valproate in a double-­blind trial (N = 50, 4 weeks).43
Aripiprazole
A double-­blind placebo-­controlled study44,45 showed aripiprazole (at doses 10 or 30mg/day) to
be significantly better than placebo at both 4 weeks (N = 296)44 and 30 weeks (N = 210).45
There was a higher incidence of extrapyramidal side effects in the treatment groups (especially
the higher dose). Weight gain was significantly more common in the treatment groups
compared with placebo (3.0kg for placebo; 6.5kg for the low-­dose arm and 6.6kg for the
high-­dose arm) at week 30.
Ziprasidone
A double-­blind placebo-­controlled trial (N = 237)46 showed ziprasidone (at flexible doses
­40–­160mg) to be more effective than placebo in reducing mean YMRS scores at 4 weeks.
Sedation and somnolence were the most common side effects, while it demonstrated a
neutral metabolic profile and no QTc prolongation. A second RCT of 171 participants showed
broadly similar outcomes.47
Asenapine
A 3-­week double-­blind placebo-­controlled study (N = 350) demonstrated statistical superiority
of asenapine over placebo for each of the doses used (2.5, 5 or 10mg BD), with significant
difference as early as day 4. However, many side effects were reported, including weight gain
of more than 7% of baseline in ­8–­12% of the asenapine group vs 1.1% in the placebo group,
metabolic changes (increase in insulin, lipids, glucose), as well as somnolence, sedation, oral
hypoaesthesia and paraesthesia.48
ALT, alanine transaminase; AST, aspartate aminotransferase; ER, extended release; MS, mood stabilisers; YMRS, Young
Mania Rating Scale.
Table 5.3  (Continued)
Prescribing in children and adolescents
CHAPTER 5
Table 5.4  Pharmacological treatments of bipolar depression in children and adolescents.
Medication
Comment
Olanzapine/
fluoxetine
combination
A large study (N = 255) of the olanzapine/fluoxetine combination (either 6/25 or 12/50mg
daily) for 8 weeks49 showed an advantage for the combination. Most frequent side effects were
weight gain (4.4kg for olanzapine/fluoxetine and 0.5kg for placebo), somnolence and
hyperlipidaemia. The olanzapine/fluoxetine combination is recommended by UK NICE
guidelines,6 along with quetiapine, as first-­line treatment for bipolar depression in children and
adolescents, as in adults. Although the olanzapine/fluoxetine combination is not currently
available as a single preparation in the UK or European Union, its effects can be achieved by
combining olanzapine and fluoxetine (e.g. 5/20 or 10/40mg).
Lurasidone
Lurasidone has been shown to be effective in bipolar depression in ­adults­­50–52 and it does not
seem to cause weight gain and other metabolic disturbances. It is also safe and effective in
treating schizophrenia in adolescents.53 Lurasidone was effective in bipolar depression in
children (­10–­17 years) both acutely12 and in a 2-­year follow-­up study.14 Dose ranged from
18.5mg (20mg) to 74mg (80mg). Lurasidone may be the preferred antipsychotic in children on
account of its good tolerability.54 In fact, a 2022 network meta-­analysis14 considered lurasidone
to be the optimal treatment for bipolar depression in youths.
Quetiapine
A small study in 32 adolescents,55 followed by a larger RCT (N = 193),56 failed to show effectiveness.
The second study had a very high placebo response, which is not usually seen in adult quetiapine
studies57 and which may reflect issues in diagnosing mood disorders in multisite studies.58 A
2022 meta-­analysis suggested quetiapine was ineffective in bipolar depression in young people.14
Lamotrigine
Lamotrigine has only modest, if any, effects in adult bipolar depression59 and it has not been
studied in RCTs for the treatment of acute bipolar depression in children and adolescents and is,
therefore, not recommended as a first-­line drug. Moreover, a placebo-­controlled randomised
withdrawal study of adjunctive lamotrigine for bipolar disorder in youth, lasting over 36 weeks,
failed to show any benefit in preventing time to occurrence of a bipolar event.60
Table 5.6  Recommended first-­line treatments for bipolar depression.*
Lurasidone
18.5mg (20mg) to 74mg (80mg) daily
Olanzapine/fluoxetine
6/25mg to 12/50mg daily
Continue acutely effective dosing regimen as prophylaxis and consider
need for lithium if not already prescribed.
Table 5.5  Recommended first-­line treatments for acute mania.
Aripiprazole
10mg daily
Risperidone
0.­5–­2.5mg daily
Olanzapine
­5–­20mg daily
Quetiapine
Up to 400mg daily
Asenapine
2.­5–­10mg twice daily
*Continue acutely effective dosing regimen as prophylaxis and consider
need for lithium if not already prescribed.

13 - References
References
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CHAPTER 5
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Prescribing in children and adolescents
CHAPTER 5
32. Masi G, et al. Lithium treatment in bipolar adolescents: a follow-­up naturalistic study. Neuropsychiatr Dis Treat 2018; 14:­2749–­2753.
33. Wagner KD, et al. A double-­blind, randomized, placebo-­controlled trial of divalproex extended-­release in the treatment of bipolar disorder
in children and adolescents. J Am Acad Child Adolesc Psychiatry 2009; 48:­519–­532.
34. Wagner KD, et al. A double-­blind, randomized, placebo-­controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and
adolescents. Am J Psychiatry 2006; 163:­1179–­1186.
35. Tohen M, et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry 2007; 164:­1547–­1556.
36. DelBello MP, et al. A double-­blind placebo-­controlled pilot study of topiramate in manic adolescents treated with olanzapine. J Child Adolesc
Psychopharmacol 2023; 33:­126–­133.
37. Haas M, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-­blind,
placebo-­controlled study. Bipolar Disord 2009; 11:­687–­700.
38. Geller B, et al. A randomized controlled trial of risperidone, lithium, or divalproex sodium for initial treatment of bipolar I disorder, manic
or mixed phase, in children and adolescents. Arch Gen Psychiatry 2012; 69:­515–­528.
39. Walkup JT, et al. Treatment of early-­age mania: outcomes for partial and nonresponders to initial treatment. J Am Acad Child Adolesc
Psychiatry 2015; 54:­1008–­1019.
40. Kowatch RA, et al. Placebo-­controlled trial of valproic acid versus risperidone in children 3-­7 years of age with bipolar I disorder. J Child
Adolesc Psychopharmacol 2015; 25:­306–­313.
41. Pathak S, et al. Efficacy and safety of quetiapine in children and adolescents with mania associated with bipolar I disorder: a 3-­week, double-­
blind, placebo-­controlled trial. J Clin Psychiatry 2013; 74:­e100–­e109.
42. Delbello MP, et al. A double-­blind, randomized, placebo-­controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am
Acad Child Adolesc Psychiatry 2002; 41:­1216–­1223.
43. Delbello MP, et al. A double-­blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child
Adolesc Psychiatry 2006; 45:­305–­313.
44. Findling RL, et al. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-­blind,
placebo-­controlled study. J Clin Psychiatry 2009; 70:­1441–­1451.
45. Findling RL, et al. Aripiprazole for the treatment of pediatric bipolar I disorder: a 30-­week, randomized, placebo-­controlled study. Bipolar
Disord 2013; 15:­138–­149.
46. Findling RL, et al. Ziprasidone in adolescents with schizophrenia: results from a placebo-­controlled efficacy and long-­term open-­extension
study. J Child Adolesc Psychopharmacol 2013; 23:­531–­544.
47. Findling RL, et al. Efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with mania in bipolar I disorder:
a randomized placebo-­controlled replication study. J Child Adolesc Psychopharmacol 2022; 32:­143–­152.
48. Findling RL, et al. Asenapine for the acute treatment of pediatric manic or mixed episode of bipolar I disorder. J Am Acad Child Adolesc
Psychiatry 2015; 54:­1032–­1041.
49. Detke HC, et al. Olanzapine/fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-­blind,
placebo-­controlled trial. J Am Acad Child Adolesc Psychiatry 2015; 54:­217–­224.
50. Loebel A, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-­blind, placebo-­controlled study.
Am J Psychiatry 2014; 171:­160–­168.
51. Suppes T, et al. Lurasidone adjunctive with lithium or valproate for bipolar depression: a placebo-­controlled trial utilizing prospective and
retrospective enrolment cohorts. J Psychiatr Res 2016; 78:­86–­93.
52. Suppes T, et  al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-­blind, placebo-­
controlled study. Am J Psychiatry 2016; 173:­400–­407.
53. Goldman R, et al. Efficacy and safety of lurasidone in adolescents with schizophrenia: a 6-­week, randomized placebo-­controlled study. J
Child Adolesc Psychopharmacol 2017; 27:­516–­525.
54. Solmi M, et al. Safety of 80 antidepressants, antipsychotics, anti-­attention-­deficit/hyperactivity medications and mood stabilizers in children
and adolescents with psychiatric disorders: a large scale systematic meta-­review of 78 adverse effects. World Psychiatry 2020; 19:­214–­232.
55. Delbello MP, et al. A double-­blind, placebo-­controlled pilot study of quetiapine for depressed adolescents with bipolar disorder. Bipolar
Disord 2009; 11:­483–­493.
56. Findling RL, et al. Efficacy and safety of extended-­release quetiapine fumarate in youth with bipolar depression: an 8 week, double-­blind,
placebo-­controlled trial. J Child Adolesc Psychopharmacol 2014; 24:­325–­335.
57. Suttajit S, et al. Quetiapine for acute bipolar depression: a systematic review and meta-­analysis. Drug Des Devel Ther 2014; 8:­827–­838.
58. Bridge JA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-­
analysis of randomized controlled trials. JAMA 2007; 297:­1683–­1696.
59. Calabrese JR, et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-­blind, placebo-­controlled clinical trials.
Bipolar Disord 2008; 10:­323–­333.
60. Findling RL, et al. Adjunctive maintenance lamotrigine for pediatric bipolar I disorder: a placebo-­controlled, randomized withdrawal study.
J Am Acad Child Adolesc Psychiatry 2015; 54:­1020–­1031.e1023.

14 - Psychosis in children and adolescents
Psychosis in children and adolescents
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Psychosis in children and adolescents
Schizophrenia is rare in children, but the incidence increases rapidly in adolescence.
A detailed developmental and physical assessment is always needed before the diagnosis is made.1,2 Early-­onset schizophrenia spectrum (EOSS) disorder is often
chronic and in the majority of cases requires long-­term treatment with antipsychotic medication.3 However, there is very limited RCT evidence for maintenance
treatment with ­antipsychotics beyond 8  weeks,4 although there are supportive
open-­label studies.5
There have been several RCTs of first-­generation antipsychotics, many of them using
very high doses and all of them showing high rates of extrapyramidal side effects
(EPSEs) and significant sedation.5 Treatment-­emergent dyskinesias can also be problematic6 even when smaller doses are used.7 First-­generation antipsychotics should be
avoided in children and adolescents.
There have also been a number of RCTs of SGAs in EOSS disorder. Olanzapine,­8–­10
risperidone,8,9,11,12 aripiprazole,13,14 quetiapine,14,15 paliperidone16 and lurasidone17 have
all been shown to be effective in the treatment of psychosis in younger people. There is
meta-­analytical evidence suggesting broadly comparable efficacy of individual SGAs,
with the exception of ziprasidone and asenapine which are relatively less effective.18,19
Importantly, neither aripiprazole nor lurasidone seems to have an effect on QT in
­adolescents.20,21 At the time of writing there is no RCT evidence supporting any additional benefit for long-­acting antipsychotic injections in younger people, although
advantages observed in adults might be assumed to be relevant in younger people.
Indeed, a 2023 review of 119 reported adolescent cases suggested good outcomes.22
Children and adolescents are at greater risk than adults for adverse effects such as
extrapyramidal symptoms, raised prolactin, sedation (even with aripiprazole14), weight
gain and metabolic effects.23 Metformin has RCT evidence for the reduction of
antipsychotic-­related overweight/obesity in children and adolescents with EOSS
­disorder, while healthy lifestyle education alone does not.24
There is evidence that clozapine is effective in treatment-­resistant psychosis in adolescents, although this population may be somewhat more prone to neutropenia and
seizures than adults.­25–­29 Based on data obtained from the treatment of younger adults,
olanzapine should probably be tried before moving to clozapine30 because there is a
palpable chance that it will be effective, although clozapine is clearly more effective
than olanzapine in adolescents.26,27
Overall, algorithms for treating psychosis in children and adolescents are the same as
those for adult patients. In the UK, NICE31 recommends oral antipsychotics in conjunction with family interventions, individual CBT and art therapy. Starting doses should be
at the lower end of, or below, the adult range. Antipsychotics should not be offered with
the aim of decreasing the risk of developing psychosis;­31–­33 they are indicated only in the
treatment of psychosis.
When prescribing antipsychotics in children and adolescents always measure baseline parameters and monitor as outlined in the guidance in the chapter on schizophrenia (see Chapter 1). For children and adolescents also include waist and hip circumference,
assessment of any movement disorders and assessment of nutritional status, diet and
level of physical activity.31

15 - References
References
Prescribing in children and adolescents
CHAPTER 5
References
Pina-­Camacho L, et al. Autism spectrum disorder and schizophrenia: boundaries and uncertainties. BJPsych Advances 2016; 22:­316–­324.
Hayes D, et al. Dilemmas in the treatment of early-­onset first-­episode psychosis. Ther Adv Psychopharmacol 2018; 8:­231–­239.
Kumra S, et al. Efficacy and tolerability of second-­generation antipsychotics in children and adolescents with schizophrenia. Schizophr Bull
2008; 34:­60–­71.
Singappuli P, et al. Antipsychotic long-­term treatment in children and young people: a systematic review and meta-­analysis of efficacy and
tolerability across mental health and neurodevelopmental conditions. CNS Spectr 2022; 27:­570–­587.
Lee ES, et al. Psychopharmacologic treatment of schizophrenia in adolescents and children. Child Adolesc Psychiatr Clin N Am 2020;
29:­183–­210.
Connor DF, et al. Neuroleptic-­related dyskinesias in children and adolescents. J Clin Psychiatry 2001; 62:­967–­974.
Campbell M, et al. Neuroleptic-­related dyskinesias in autistic children: a prospective, longitudinal study. J Am Acad Child Adolesc Psychiatry
1997; 36:­835–­843.
Sikich L, et al. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-­blind, randomized, 8-­week trial.
Neuropsychopharmacology 2004; 29:­133–­145.
Sikich L, et al. Double-­blind comparison of first-­ and second-­generation antipsychotics in early-­onset schizophrenia and schizo-­affective disorder: findings from the treatment of early-­onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165:­1420–­1431.
Kryzhanovskaya L, et  al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-­week, randomized, double-­blind, placebo-­
controlled trial. J Am Acad Child Adolesc Psychiatry 2009; 48:­60–­70.
Haas M, et al. A 6-­week, randomized, double-­blind, placebo-­controlled study of the efficacy and safety of risperidone in adolescents with
schizophrenia. J Child Adolesc Psychopharmacol 2009; 19:­611–­621.
Haas M, et al. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-­blind study. Br J Psychiatry 2009;
194:­158–­164.
Findling RL, et al. A multiple-­center, randomized, double-­blind, placebo-­controlled study of oral aripiprazole for treatment of adolescents
with schizophrenia. Am J Psychiatry 2008; 165:­1432–­1441.
Pagsberg AK, et al. Quetiapine extended release versus aripiprazole in children and adolescents with first-­episode psychosis: the multicentre,
double-­blind, randomised tolerability and efficacy of antipsychotics (TEA) trial. Lancet Psychiatry 2017; 4:­605–­618.
Findling RL, et al. Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-­week, double-­blind, placebo-­
controlled trial. J Child Adolesc Psychopharmacol 2012; 22:­327–­342.
Singh J, et  al. A randomized, double-­blind study of paliperidone extended-­release in treatment of acute schizophrenia in adolescents.
Biol Psychiatry 2011; 70:­1179–­1187.
Arango C, et al. Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature
review and network meta-­analysis. Eur Child Adolesc Psychiatry 2019; 29:­1195–­1205.
Pagsberg AK, et al. Acute antipsychotic treatment of children and adolescents with schizophrenia-­spectrum disorders: a systematic review and
network meta-­analysis. J Am Acad Child Adolesc Psychiatry 2017; 56:­191–­202.
Lopez-­Morinigo JD, et al. Pharmacological treatment of early-­onset schizophrenia: a critical review, evidence-­based clinical guidance and
unmet needs. Pharmacopsychiatry 2022; 55:­233–­245.
Jensen KG, et al. Change and dispersion of QT interval during treatment with quetiapine extended release versus aripiprazole in children and
adolescents with first-­episode psychosis: results from the TEA trial. Psychopharmacology (Berl) 2018; 235:­681–­693.
Goldman R, et al. Efficacy and safety of lurasidone in adolescents with schizophrenia: a 6-­week, randomized placebo-­controlled study.
J Child Adolesc Psychopharmacol 2017; 27:­516–­525.
Baeza I, et al. What role for long-­acting injectable antipsychotics in managing schizophrenia spectrum disorders in children and adolescents?
A systematic review. Paediatr Drugs 2023; 25:­135–­149.
Sunshine A, et al. Practitioner review: psychosis in children and adolescents. J Child Psychol Psychiatry 2023; 64:­980–­988.
Correll CU, et al. Metformin add-­on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial. World Psychiatry 2020; 19:­69–­80.
Kumra S, et al. Childhood-­onset schizophrenia. A double-­blind clozapine-­haloperidol comparison. Arch Gen Psychiatry 1996; 53:­1090–­1097.
Shaw P, et al. Childhood-­onset schizophrenia: a double-­blind, randomized clozapine-­olanzapine comparison. Arch Gen Psychiatry 2006;
63:­721–­730.
Kumra S, et al. Clozapine and ‘high-­dose’ olanzapine in refractory early-­onset schizophrenia: a 12-­week randomized and double-­blind comparison. Biol Psychiatry 2008; 63:­524–­529.
Schneider C, et al. Systematic review of the efficacy and tolerability of clozapine in the treatment of youth with early onset schizophrenia.
Eur Psychiatry 2014; 29:­1–­10.
Adnan M, et al. Clozapine for management of childhood and adolescent-­onset schizophrenia: a systematic review and meta-­analysis. J Child
Adolesc Psychopharmacol 2022; 32:­2–­11.
Agid O, et al. An algorithm-­based approach to first-­episode schizophrenia: response rates over 3 prospective antipsychotic trials with a
­retrospective data analysis. J Clin Psychiatry 2011; 72:­1439–­1444.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management. Clinical Guidance [CG155]. 2013 (last updated October 2016, last checked October 2023); https://www.nice.org.uk/guidance/cg155.
Catalan A, et al. Annual research review: prevention of psychosis in ­adolescents –­ systematic review and meta-­analysis of advances in detection, prognosis and intervention. J Child Psychol Psychiatry 2021; 62:­657–­673.
Lång U, et al. Systematic review and meta-­analysis: psychosis risk in children and adolescents with an at-­risk mental state. J Am Acad Child
Adolesc Psychiatry 2022; 61:­615–­625.

16 - Anxiety disorders in children and adolescents
Anxiety disorders in children and adolescents

17 - Diagnostic issues
Diagnostic issues

18 - Clinical guidance
Clinical guidance

19 - Prescribing for anxiety disorders in children
Prescribing for anxiety disorders in children and adolescents
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Anxiety disorders in children and adolescents
Diagnostic issues
Fear and worry are common in children and they are part of normal development. At
the same time, anxiety disorders often begin in childhood and adolescence1 and they
are the most common psychiatric disorders in this age group, with overall prevalence
between 8% and 30% depending on the impairment cut-­offs used.2 Anxiety disorders
may be even more common in children with neurodevelopmental disorders.3
In children, the more obvious clinical presentation with distress and avoidance may
be masked by prominent behavioural symptoms (e.g. irritability and angry outbursts
linked to avoidance). Therefore, the assessment and treatment of anxiety disorders in
children need to be undertaken by clinicians who can discriminate normal, developmentally appropriate worries, fears and shyness from anxiety disorders that significantly impair a child’s functioning, and who can appreciate developmental variations in
the presentation of symptoms.
Clinical guidance
Anxiety symptoms in children and adolescents often improve with age, presumably in
parallel to the development of the prefrontal cortex and, in particular, executive function. However, anxiety disorders are distressing and impairing conditions that need to
be treated promptly. Chronic stress mediators may have significant impact on brain
development4 and functional impairment linked to anxiety symptoms may prevent
young people from accessing normative experiences that are critical for social, emotional and cognitive development. Finally, early and effective treatment may prevent
continuity of psychopathology into adulthood: for example, young people with anxiety
disorders are three times more likely to have anxiety and depression in adult life compared with non-­anxious youth.5
Guidelines for the treatment of anxiety disorders in children and adolescents have
been made available in the UK and the USA. NICE guidelines focus on the treatment of
social anxiety disorder in children and adolescents, suggesting the use of cognitive behavioural therapy and cautioning against the routine use of pharmacological treatment for
social anxiety in this age group.6 Guidelines from AACAP cover the treatment of all anxiety disorders except post-­traumatic stress disorder (PTSD) and obsessive compulsive
disorder (OCD) (which are classified separately according to DSM).7 AACAP guidelines
suggest multimodal treatment including psychoeducation, psychotherapy (e.g. a
12-­session course of exposure-­based CBT) and pharmacotherapy. Drug treatment is
endorsed for moderate-­to-­severe anxiety symptoms, when impairment makes participation in psychotherapy difficult, or when psychotherapy leads to only partial response.
Prescribing for anxiety disorders in children and adolescents
Before prescribing
■
■Exclude other diagnoses: Anxiety symptoms can be mimicked by a range of psychiatric disorders including depression (inattention, sleep problems), bipolar disorder
(­irritability, sleep problems, restlessness), oppositional-­defiant disorder (­irritability,
Prescribing in children and adolescents
CHAPTER 5
oppositional behaviour), psychotic disorders (social withdrawal, restlessness),
ADHD (inattention, restlessness), autism spectrum disorder (social withdrawal,
poor social skills, repetitive behaviours and routines) and learning disabilities.
They may also be mimicked by a range of endocrine (hyperthyroidism, hypoglycaemia, phaeo­chromocytoma), neurological (migraine, seizures, delirium, brain
tumours), cardiovascular (cardiac arrhythmias) and respiratory (asthma) conditions and lead intoxication. Anxiety-­like symptoms can be observed in response to
several drugs and ­substances including anti-­asthma medications, sympathomimetics, ­steroids, SSRIs, antipsychotics (akathisia), diet pills, cold medicines, caffeine
and energy drinks.
■
■Beware contraindications to SSRIs and potential interactions.
■
■Measure baseline severity: Use structured interviews including the Anxiety Disorders
Interview Schedule (ADIS) and the Kiddie-­Schedule for Affective Disorders and
Schizophrenia (Kiddie-­SADS); questionnaires including the Revised Children’s
Anxiety and Depression Scale (RCADS), Screen for Child Anxiety and Related
Emotional Disorders (SCARED) or the Multidimensional Anxiety Scale for Children
(MASC); and measures of functional impairment including the Children’s Global
Assessment Scale (CGAS).
■
■Obtain consent: Discuss treatment with the young person and the family (e.g. name
of medication, starting/estimated ending dose, titration timeline, possible side effects
and strategies to monitor/minimise them, strategies to monitor progress, interventions for treatment-­resistant cases). Document consent in writing.
What to prescribe
■
■SSRIs: These are the medications of choice for the treatment of anxiety disorders in
children and adolescents. SSRI treatment is at least as effective as non-­drug treatments.8 A 2019 meta-­analysis identified seven short-­term RCTs (<16 weeks; n treatment = 446, n control = 386) testing the efficacy of SSRIs (fluoxetine, fluvoxamine,
paroxetine, sertraline) on changes in severity of anxiety in young people (Clinical
Global Impression I [CGI-­I] scale). The odds ratio (vs placebo) of overall treatment
response was 4.6 (95%CI = 3.­1–­7.5) and, in anxiety symptoms specifically, 5.2
(95%CI = 2.­8–­8.8).9 The Childhood Anxiety Multimodal Study (CAMS) showed
that monotherapy with sertraline (55% response) is as effective as CBT for anxiety
(60% response) and better than placebo (24% response), and that combined therapy
with sertraline and CBT is most likely to be successful (81% response).10 A 2017 network meta-­analysis found that SSRIs significantly reduce clinician-­reported and
parent-­reported (but not child-­reported) anxiety symptoms and increased rates of
remission.11 Another network meta-­analysis found that the likelihood of treatment
response was higher for SSRI compared with the following other medications;9
a standard meta-­analysis showed that clinically significant treatment effects ­typically
emerge by week 6 of treatment, and that SSRIs are associated with more rapid and
greater improvement than these other medications.12 The most recent meta-­analysis
(11 studies, 2122 participants [2023])13 suggests broadly similar efficacy for SSRIs/­
serotonin–­noradrenaline reuptake inhibitors (SNRIs). With regard to tolerability,
SSRIs are the best tolerated class of medications, particularly escitalopram and
fluoxetine.14
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Sertraline, fluoxetine and fluvoxamine have been approved by the US FDA for
treatment of paediatric OCD, and fluoxetine and escitalopram have been approved
for treatment of paediatric depression. The FDA issued in 2004 a black box warning
for concerns related to worsening of depression, agitation and suicidal ideation linked
to SSRIs. These concerns were based on a review of studies of adolescents with
depression rather than young people with anxiety.
■
■SNRIs: Venlafaxine was tested in two short-­term RCTs (n treatment = 294, n ­control =
311), duloxetine was tested in one short-­term RCT (n treatment = 135, n control = 137)
and atomoxetine was tested in one short-­term RCT. The overall odds ratio of treatment
response for SNRIs was 2.4 (95%CI = 1.­7–­3.6) over placebo.9 However, SNRIs did not
show statistically significant effects on improvement in anxiety symptoms over placebo.9
The network meta-­analysis mentioned earlier found that SNRIs significantly reduce
clinician-­reported (but not parent-­reported or child-­reported) anxiety symptoms.11 SSRIs
are more effective and better tolerated9 so SNRIs could be considered a third-­line
­treatment for anxiety disorders when two trials with different SSRIs prove ineffective.
■
■Others: The 5HT1A agonist buspirone has been examined in one short-­term RCT
(n treatment = 334, n control = 225) and found not to be effective.15 The alpha2
­agonist guanfacine was evaluated in one short-­term RCT (n treatment = 62, n control
= 21) and found to be associated with an increased odds ratio for treatment response
(5.6 [95%CI = 1.­4–­26.8]) but not for improvement in anxiety symptoms.16
■
■Neither benzodiazepine nor tricyclic antidepressant use is supported by controlled
trials in children.9 Benzodiazepine may also lead to paradoxical disinhibition in some
children. Nevertheless, use of longer-­acting benzodiazepines is at times considered in
clinical practice either to alleviate disabling anxiety during initial titration of SSRIs or
for rapid tranquillisation.
Table 5.7 lists the doses for treating anxiety disorders in children and adolescents.
After prescribing
Acute phase
■
■Start at the lowest available dose.
■
■Monitor side effects. SSRIs are generally well tolerated during treatment for anxiety
disorders in young people. Psychological side effects include worsening of anxiety
symptoms, agitation and disinhibition. Physical side effects including gastrointestinal
symptoms (e.g. nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, constipation), headache, increased motor activity and insomnia may occur, often in mild and
transient form.
■
■After 1 week of treatment with SSRIs (2 weeks for SNRIs) when the child is compliant with medications and does not manifest more than minimal side effects, titrate
incrementally with weekly intervals to the minimal therapeutic dose.
■
■Monitor side effects and response (e.g. RCADS, SCARED, MASC, CGAS, CGI-­I)
frequently and systematically.
■
■Dosage for treatment with SSRIs is often similar to dosage in adults because of faster
metabolism in children.
■
■Therapeutic effect should appear by ­6–­8 weeks of treatment. It is important to communicate this to families.
■
■If partial or non-­response, consider accuracy of diagnosis, adequacy of medication
trial and compliance of patient.
Prescribing in children and adolescents
CHAPTER 5
■
■To improve response, consider adding CBT, changing medication (e.g. switch SSRIs,
other classes) or combining medications (e.g. for comorbidities, to treat side effects,
to potentiate action). Augmentation strategies with buspirone, benzodiazepines,
­atypical antipsychotics and stimulant medications have been proposed but lack
empirical support.7
Maintenance phase
■
■Continue maintenance treatment for at least 1 year of stable improvement.
■
■Monitor response and side effects regularly.
Discontinuation phase
■
■Because of lack of information on long-­term safety and possible improvement in symptoms with age and learning, consider discontinuing treatment after a period of stable
improvement. A trial of medication withdrawal should be started at a period of low
stress/demands. Discontinuation should also be considered if the medication is no longer
working or the side effects are too severe. Taper SSRIs slowly (e.g. 25% of previous dose
weekly) to minimise the risk of discontinuation symptoms. Monitor closely for recurrence of symptoms/relapse and, if deterioration is noted, consider restarting medication.
Table 5.7  Typical dosage of medications for treatment of anxiety disorders in children
and adolescents.
Medication
Starting dose (mg)
Dose range (mg/day)
SSRI
Sertraline
12.­5–­25
­25–­200
Fluoxetine
­5–­10
­10–­60
Fluvoxamine
12.­5–­25
­50–­200
(bd if >50)
Paroxetine
­5–­10
­10–­40
Citalopram*
­5–­10
­10–­40
SNRI
Venlafaxine XR
37.5
37.­5–­225
Duloxetine
­30–­120
Alpha2 agonist
Guanfacine
­1–­6
5HT1A partial agonist
Buspirone*
5 tds
­15–­60
Benzodiazepine (prn)
Clonazepam*
0.­25–­0.5
–­
Lorazepam*
0.­5–­1
–­
Note: always check dose with latest formal guidance, e.g. British National Formulary for
Children (in the UK).
*Treatments not supported by randomised controlled trial evidence.
bd, twice daily; prn, as required; tds, three times daily.

20 - References
References
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CHAPTER 5
Pre-school children
Treatment of anxiety disorders in pre-­school children must routinely focus on
­psychotherapy. In rare cases when a very young child has extreme ongoing symptoms
and impairment, clinicians should reconsider diagnosis and case formulation, and reassess the adequacy of the psychotherapy trial. There are no RCTs of pharmacological
interventions for anxiety in pre-­school children, but case reports suggest a potential
benefit of fluoxetine and buspirone.17 Any prescription in pre-­school children is
off-­label.18
References
Kessler RC, et al. Lifetime prevalence and age-­of-­onset distributions of DSM-­IV disorders in the National Comorbidity Survey Replication.
Arch Gen Psychiatry 2005; 62:­593–­602.
Merikangas KR, et al. Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey ­Replication –­
Adolescent Supplement (NCS-­A). J Am Acad Child Adolesc Psychiatry 2010; 49:­980–­989.
Simonoff E, et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a
population-­derived sample. J Am Acad Child Adolesc Psychiatry 2008; 47:­921–­929.
Danese A, et al. Adverse childhood experiences, allostasis, allostatic load, and age-­related disease. Physiol Behav 2012; 106:­29–­39.
Pine DS, et al. The risk for early-­adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen
Psychiatry 1998; 55:­56–­64.
National Institute for Health and Clinical Excellence. Social anxiety disorder: recognition, assessment and treatment. Clinical Guidance
[CG159]. 2013 (last updated 2017, last checked December 2023); https://www.nice.org.uk/guidance/cg159.
Connolly SD, et al. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child
Adolesc Psychiatry 2007; 46:­267–­283.
Arnardóttir A, et al. Comparative effectiveness of cognitive behavioral treatment, serotonin, and serotonin noradrenaline reuptake inhibitors
for anxiety in children and adolescents: a network meta-­analysis. Nord J Psychiatry 2023; 77:­118–­126.
Dobson ET, et al. Efficacy and tolerability of pharmacotherapy for pediatric anxiety disorders: a network meta-­analysis. J Clin Psychiatry
2019; 80:17r12064.
Walkup JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med 2008; 359:­2753–­2766.
Wang Z, et al. Comparative effectiveness and safety of cognitive behavioral therapy and pharmacotherapy for childhood anxiety disorders:
a systematic review and meta-­analysis. JAMA Pediatrics 2017; 171:­1049–­1056.
Strawn JR, et al. The impact of antidepressant dose and class on treatment response in pediatric anxiety disorders: a meta-­analysis. J Am Acad
Child Adolesc Psychiatry 2018; 57:­235–­244.e232.
Stefánsdóttir ÍH, et al. Efficacy and safety of serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRI) for
children and adolescents with anxiety disorders: a systematic review and meta-­analysis. Nord J Psychiatry 2023; 77:­137–­146.
Solmi M, et al. Safety of 80 antidepressants, antipsychotics, anti-­attention-­deficit/hyperactivity medications and mood stabilizers in children
and adolescents with psychiatric disorders: a large scale systematic meta-­review of 78 adverse effects. World Psychiatry 2020; 19:­214–­232.
Strawn JR, et al. Buspirone in children and adolescents with anxiety: a review and Bayesian analysis of abandoned randomized controlled
trials. J Child Adolesc Psychopharmacol 2018; 28:­2–­9.
Strawn JR, et al. Extended release guanfacine in pediatric anxiety disorders: a pilot, randomized, placebo-­controlled trial. J Child Adolesc
Psychopharmacol 2017; 27:­29–­37.
Gleason MM, et al. Psychopharmacological treatment for very young children: contexts and guidelines. J Am Acad Child Adolesc Psychiatry
2007; 46:­1532–­1572.
Mohatt J, et al. Treatment of separation, generalized, and social anxiety disorders in youths. Am J Psychiatry 2014; 171:­741–­748.

21 - Obsessive compulsive disorder (OCD) and body
Obsessive compulsive disorder (OCD) and body dysmorphic disorder (BDD) in children and adolescents

22 - Drug treatment in obsessive compulsive disord
Drug treatment in obsessive compulsive disorder (OCD)

23 - Drug treatment in body dysmorphic disorder (B
Drug treatment in body dysmorphic disorder (BDD)
Prescribing in children and adolescents
CHAPTER 5
Obsessive compulsive disorder (OCD) and body dysmorphic disorder
(BDD) in children and adolescents
The treatment of OCD and BDD in children and young people largely follows the same
principles as those for adults.1 BDD is recognised by both DSM-­5 and ICD-­11 as one of
the obsessive compulsive disorders. Cognitive behavioural therapy is effective for both
conditions in this age group and is recommended in the UK by NICE as the first-­choice
treatment, although it may be combined with medication for optimal effect.2
While CBT is the mainstay of treatment for OCD and BDD, medication alone may
be the only viable therapeutic option in some cases. Some children are reluctant to
engage with CBT, some may find it difficult to access or they may have very poor
insight. This last situation may arise in the autism spectrum disorder alongside comorbid OCD or BDD. Insight in BDD is characteristically poorer than in OCD, with up to
50% of cases having beliefs about their appearance which are of delusional intensity.
This too can affect motivation to engage with psychological therapy. Where medication
is being used as the only evidence-­based treatment, it is essential that this remains under
review so that motivation and ability to engage with CBT are regularly revisited.
Drug treatment in obsessive compulsive disorder (OCD)
Sertraline (from age 6 years) and fluvoxamine (from age 8 years) are the SSRIs licensed in
the UK for the treatment of OCD in young people. Studies have established the efficacy
of SSRIs in the child and adolescent population in several placebo-­controlled trials.­3–­5
SSRIs have a medium to large effect size in the treatment of OCD in children and
young people.6 A meta-­analysis of 12 RCTs of pharmacotherapy in young people under
19 years of age showed that medication is consistently more effective than placebo.
Fluoxetine is the most efficacious SSRI for treatment of depression.7 Many young people presenting with OCD have a diagnosis of comorbid depression, so fluoxetine could
be considered as an alternative SSRI to sertraline or fluvoxamine in these cases.
Paroxetine is not recommended for use in children and young people.
Clomipramine remains a useful drug for some individuals and is debatably more
efficacious than the SSRIs in treating OCD in children and young people.8 However,
clomipramine’s side effect profile (sedation, dry mouth, potential for cardiac side
effects) tends to limit its use in this age group and, as a consequence, SSRIs remain the
first-­line choice in OCD.
SNRIs are not recommended for treatment of OCD in children and young people,
with no clear evidence of efficacy and poorer tolerability than SSRIs.
Drug treatment in body dysmorphic disorder (BDD)
No treatment is licensed in the UK for either adults or children with BDD. However,
evidence shows significant improvements with SSRIs, both in terms of BDD symptoms,
suicidality and often comorbid depressive symptoms (­80–­90% of people with BDD
also have a comorbid diagnosis of depression9). In the UK, NICE recommends fluoxetine as the SSRI of choice for treating BDD in children. Although BDD cases have delusional intensity beliefs about their appearance, antipsychotics are not effective and are

24 - Prescribing SSRIs in children
Prescribing SSRIs in children

25 - NICE guidelines for the assessment and treatm
NICE guidelines for the assessment and treatment of OCD and BDD
588
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
not recommended. Research in adult patients shows that BDD patients with delusional
intensity appearance beliefs are as likely to respond to SSRI monotherapy as are non-­
delusional patients.9
Prescribing SSRIs in children
In 2004, the UK MHRA cautioned against the use of SSRIs in children and young people owing to a possible increased risk of suicidal ideation.10 Careful re-­analysis of treatment data suggests that SSRIs are clearly more efficacious in OCD than they are in
moderate depressive episodes in children and young people.6 Investigators concluded
that within the paediatric OCD group, the pooled risk for suicidal ideation and attempts
was less than 1% across all studies. This of course is an important risk and should be
explained and carefully monitored. Nonetheless, the naturalistic course of untreated
OCD and BDD is that patients tend not to spontaneously remit, and they have tremendous associated morbidity. It is also known that untreated OCD and BDD are associated with a 10-­fold increased risk of completed suicide compared with the general
population in OCD.9,11 The risk of suicide in BDD is higher, with roughly one in three
patients with BDD attempting suicide.12 These factors need to be carefully considered
and discussed with the patient and their carers or family in making informed choices
about treatment.
On occasion, medications other than sertraline and fluvoxamine may be used
‘off-­label’ with the appropriate and suitable cautions. NICE guidance13 for the treatment of OCD recommends the use of maximum tolerated dose strategies of two
SSRIs before the use of clomipramine, owing to the latter drug’s greater propensity
for side effects and need for cardiac monitoring. The alternative to clomipramine is
augmentation with a low-­dose antipsychotic. Factors guiding the choice of other
medications may include issues such as the presence of other disorders; response to a
certain drug in other family members; and cost and availability. Compliance with
medication can be an issue with some young people, which can guide the choice of
preparation. For instance, young people with poor compliance may be better suited
to treatment with fluoxetine considering its long half-­life compared with other SSRIs.
A 2020 meta-­analysis showed fluoxetine and sertraline to be more effective in OCD
treatment than fluvoxamine.8 Some children can find tablets or capsules hard to
swallow and the availability of licensed liquid formulations is limited in most
countries.
NICE guidelines for the assessment and treatment of OCD and BDD
NICE published guidelines in 2005 on evidence-­based treatment options for OCD and
BDD for young people and adults.13 NICE recommends a ‘stepped care’ model, with
increasing intensity of treatment according to clinical severity and complexity.13
Assessment of the severity and impact of OCD or BDD can be aided by the use of the
Children’s Yale-­Brown Obsessive Compulsive Scale (CY-­BOCS) or BDD-­YBOCS questionnaires, respectively, or other quantitative measures, both at baseline and as a helpful
monitoring tool.14
The summary treatment algorithm from the NICE guideline is shown in Figure 5.1.

26 - Initiation of treatment with medication
Initiation of treatment with medication
Prescribing in children and adolescents
CHAPTER 5
Initiation of treatment with medication
Clomipramine and SSRIs show a similar incremental effect on obsessions and compulsions from as early as ­1–­2 weeks after initiation and placebo-­referenced improvements
continue for at least 24 weeks. In some cases, a positive impact on mood may be seen
before the initial changes in OCD symptoms.16 In the UK, NICE therefore recommends
two treatment trials of SSRIs for OCD and BDD of 3 months and increasing towards
the maximum tolerated effective dosage. Carefully explaining these temporal effects to
patients can be important in sustaining compliance. In addition, the earliest signs of
improvement may be apparent to an informant before the patient. Use of an observer-­
rated quantitative measure such as the CY-­BOCS or BDD-­YBOCS may therefore be
helpful to monitor progress in clinical settings.17 Expert consensus typically suggests
starting at the lowest dose known to be effective, titrating upwards and waiting for up
to 12 weeks before evaluating effectiveness.18 Careful dose titration is particularly recommended if there is insufficient clinical response. In clinical practice a balance must
clearly be struck between tolerability and the rate of dosage increase. It is worth noting
that the majority of young people with OCD will require a higher dose of SSRI, and as
such it may well be clinically indicated to increase the dose more quickly after starting
an SSRI.
Mild
functional impairment
Moderate or severe
functional impairment
Consider guided self-help support
and information for family/carers
Ineffective or refused
Ineffective or refused
Consider an SSRI (with careful monitoring)
Multidisciplinary review
Consider either (especially if previous good response to):
Different SSRI
Clomipramine
SSRI + ongoing CBT (including ERP):
Consider use in 8–11-year age group
Offer to 12–18-year age group
Carefully monitor for adverse events, especially at start of treatment
Offer CBT (+ERP); involve family/carers
(individual or group formats)
Figure 5.1  Treatment options for children and young people with obsessive compulsive disorder. CBT, cognitive
behaviour therapy; ERP, exposure and response prevention. Adapted from NICE guidance.13 Reprinted with
permission.15

27 - Treatment refractory OCD and BDD in children
Treatment-refractory OCD and BDD in children
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CHAPTER 5
Treatment-­refractory OCD and BDD in children
Evidence from randomised trials suggests that up to three-­quarters of medicated
patients have an adequate response to treatment. About a quarter of children and young
people with OCD will therefore fail to respond to an initial SSRI, administered for at
least 12 weeks at the maximum tolerated dose, in combination with an adequate trial
of CBT and exposure and response prevention (ERP). These children should be reassessed and compliance clarified, and it should be ensured that clinical comorbidities are
not being missed. In such cases, children and young people should usually have additional trials of at least one other SSRI. Research suggests that approximately 40%
respond to a second SSRI in both OCD and BDD.19 Following this, if the response is
limited, consideration should be given to referral to a specialist centre.
In OCD, trials of clomipramine may be considered and/or augmentation with a low
dose of risperidone or aripiprazole.13,20 Augmentation with antipsychotics is not recommended in the treatment of BDD.
The combination of fluvoxamine and clomipramine has been used in refractory
cases21,22 but, given the dangers of serotonin syndrome, these regimens should be
reserved for specialist centres. Improved efficacy seems to be linked to the altering of
the metabolism of clomipramine by fluvoxamine.
There is evidence that low-­dose antipsychotic augmentation of SSRI treatment as an
off-­label therapy can benefit patients whose response to treatment has been inadequate
despite at least 3 months of two maximal tolerated separate SSRIs. There is a more
robust evidence base in adult cohorts than in younger people. Only a third of treatment-­
resistant adult cases of OCD showed a meaningful response to this augmentation strategy. Small studies conducted on children and young people showed a clinical improvement
for OCD, with a larger evidence base available for aripiprazole compared with
risperidone.­23–­25 A ­6–­8-­week trial of low-­dose antipsychotic augmentation is typically
sufficient to assess efficacy. In practice, doses no larger than aripiprazole 2.­5–­5mg daily
or risperidone 0.5mg daily should be used. It is important to discontinue the anti­
psychotic if no response is noted after this trial of SSRI augmentation. Antipsychotics
alone are not efficacious treatments for obsessive compulsive disorders.
Often children and young people whose OCD or BDD has been difficult to treat have
comorbidities such as autism spectrum disorder, ADHD or tic disorders. The response
to medication can be differentially affected by these comorbidities. For instance, patients
with tic disorders may benefit somewhat more from augmentation with second-­
generation antipsychotics.26 Untreated ADHD can also commonly interfere with
engagement with CBT due to poor focus. Very often efforts to address ADHD with
appropriate treatments including medication can dramatically improve engagement
with CBT. However, caution is required with regard to stimulant use, particularly for
young people who are not ‘fighting back’ against compulsions. In this group, one can
see an increase in compulsions as concentration improves.
Careful clinical review and reformulation are important in treatment-­resistant OCD
and BDD. Comorbidities and wider psychosocial factors need to be considered for their
impact on the treatment response overall. The evidence base around systemic factors
and their application in OCD is poor. Very often clinical experience shows that it can
be vital to support families and carers during treatment.
Alternative experimental and adult treatments are given in Tables 5.8 and 5.9.

28 - Duration of treatment and long term follow up
Duration of treatment and long-term follow-up
Prescribing in children and adolescents
CHAPTER 5
Duration of treatment and long-­term follow-up
Untreated OCD runs a chronic course. A series of adult studies have shown that discontinuation of medication tends to result in a varying degree of symptomatic relapse.27
Some authors have suggested that those with comorbidities are at the greatest risk of
relapse.28 Given that studies frequently exclude cases with additional comorbidities, it
is likely that the relapse rates have been underestimated. In the UK, NICE guidelines
recommend that if a young person has responded to medication, treatment for OCD or
BDD should continue for at least 6 months after remission. This recommendation was
based on clinical consensus rather than the product of carefully conducted research trials. Clinical experience would also suggest that when discontinuation of treatment is
attempted it should be done slowly, cautiously and in a transparent manner with the
patient and their family. Once again, the careful use of clinical outcome measures
should be considered when stopping medication. There is a considerable evidence base
and expert clinical consensus suggesting that discontinuing medication is associated
with a deterioration in symptoms of either OCD or BDD. Increasingly adults and young
people are being counselled to consider whether they wish to remain on SSRI medication longer term to mitigate the substantial risk of relapse of OCD or BDD symptoms.
Thoughtful and honest discussion about the potential risks of stopping medication
should be an active part of any care plan in OCD.
Individuals with developmental disabilities often struggle to generalise the lessons
taken from successful CBT. They also have a higher propensity for adverse effects such
as activation syndromes with SSRIs, therefore titration may need to be slower.29 It is
important that throughout childhood, adolescence and into adult life individuals with
OCD or BDD should have rapid access to healthcare professionals, treatment opportunities and other support as needed. NICE recommends that if relapse occurs, people
with OCD or BDD should be seen as soon as possible rather than placed on a routine
waiting list because of the propensity for rapid deterioration of symptoms.
Table 5.8  Alternative and experimental treatment of OCD in children and young people.
Treatment
Comment
Aripiprazole augmentation of SSRI
Evidence of clinical improvement in children and young people with
OCD23,24,26,30
No evidence base for use in BDD
Risperidone augmentation of SSRI
Fewer studies than aripiprazole augmentation in children and young
people25
Fluvoxamine with low-­dose
clomipramine
Better tolerated than clomipramine monotherapy31
N-­acetylcysteine (NAC)
Limited evidence suggests children and adolescents with OCD refractory
to SSRIs or CBT may benefit from NAC augmentation.32
Memantine
Limited evidence suggests potential ­benefit.­­33–35
Lamotrigine
Case studies have reported response.36
BDD, body dysmorphic disorder; CBT, cognitive behavioural therapy; OCD, obsessive compulsive disorder.

29 - References
References
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The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
References
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and posttraumatic stress ­disorders –­ version 3. Part II: OCD and PTSD. World J Biol Psychiatry 2023; 24:­118–­134.
Tao Y, et al. Comparing the efficacy of pharmacological and psychological treatment, alone and in combination, in children and adolescents
with obsessive-­compulsive disorder: a network meta-­analysis. J Psychiatr Res 2022; 148:­95–­102.
Pediatric OCD Treatment Study Team (POTS). Cognitive-­behavior therapy, sertraline, and their combination for children and adolescents
with obsessive-­compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 2004; 292:­1969–­1976.
Geller DA, et al. Which SSRI? A meta-­analysis of pharmacotherapy trials in pediatric obsessive-­compulsive disorder. Am J Psychiatry 2003;
160:­1919–­1928.
March JS, et al. Treatment benefit and the risk of suicidality in multicenter, randomized, controlled trials of sertraline in children and adolescents. J Child Adolesc Psychopharmacol 2006; 16:­91–­102.
Garland J, et al. Update on the use of SSRIs and SNRIs with children and adolescents in clinical practice. J Can Acad Child Adolesc Psychiatry
2016; 25:­4–­10.
National Institute for Clinical Excellence. Depression in children and young people: identification and management. NICE Guideline
[NG134]. 2019 (last checked December 2023); https://www.nice.org.uk/guidance/ng134.
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Psychiatry 2020; 11:717.
Phillips KA, et al. Treating body dysmorphic disorder with medication: evidence, misconceptions, and a suggested approach. Body Image
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Weller IVD, et al. Report of the CSM expert working group on the safety of selective serotonin reuptake inhibitor antidepressants. 2005;
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Fernández de la Cruz L, et al. Suicide in obsessive-­compulsive disorder: a population-­based study of 36 788 Swedish patients. Mol Psychiatry
2017; 22:­1626–­1632.
Pellegrini L, et al. Suicidality in patients with obsessive-­compulsive and related disorders (OCRDs): a meta-­analysis. Compr Psychiatry 2021;
108:152246.
Table 5.9  Treatments of OCD used in adults that may be effective in children.
Treatment
Comment
Topiramate augmentation
of SSRI
Case studies suggest this may be beneficial and one RCT showed an effect for
compulsions but not obsessions.37,38 Other trials have not found it to be effective.39
Not to be used in female adolescents.
High-­dose SSRI
(with ECG monitoring)
Higher than licensed maximum dose SSRI associated with clinical improvement and well
tolerated in a retrospective case note survey, double-­blind trial and open-­label ­study­­40–42
SNRIs
Duloxetine shown to be as effective as sertraline in a small RCT, and an open-­label
trial suggested it could reduce symptoms of OCD43,44
Mirtazapine
Superior to placebo in an open trial45
Pregabalin
Augmentation of sertraline was more effective than augmentation with placebo.46
5HT3 antagonists
Ondansetron is effective as add-­on treatment.47 Note risk of QT prolongation
Ketamine IV
Case report showed rapid resolution of symptoms48
Tolcapone (catechol-Omethyltransferase inhibitor)
One small trial showed benefit over placebo.49
Methylphenidate
Small study showed some benefit for OCD in combination with fluvoxamine50
Deep brain stimulation
Could be effective treatment for resistant OCD.51
Transcranial magnetic
stimulation (TMS)
Meta-­analysis showed that TMS can reduce the severity of OCD.52
Prescribing in children and adolescents
CHAPTER 5
13. National Institute for Clinical Excellence. Obsessive-­compulsive disorder and body dysmorphic disorder: treatment. Clinical Guideline
[CG31]. 2005 (last checked December 2023); https://www.nice.org.uk/guidance/cg31.
14. Fernández de la Cruz L, et al. Suicide in obsessive-­compulsive disorder: a population-­based study of 36 788 Swedish patients. Mol Psychiatry
2017; 22:­1626–­1632.
15. Heyman I, et al. Obsessive-­compulsive disorder. BMJ 2006; 333:­424–­429.
16. Scahill L, et al. Children’s Yale-­Brown Obsessive Compulsive Scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 1997;
36:­844–­852.
17. Baldwin DS, et al. Evidence-­based pharmacological treatment of anxiety disorders, post-­traumatic stress disorder and obsessive-­compulsive
disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28:­403–­439.
18. Bloch MH, et al. Assessment and management of treatment-­refractory obsessive-­compulsive disorder in children. J Am Acad Child Adolesc
Psychiatry 2015; 54:­251–­262.
19. Grados M, et al. Pharmacotherapy in children and adolescents with obsessive-­compulsive disorder. Child Adolesc Psychiatr Clin N Am 1999;
8:­617–­634, x.
20. Bloch MH, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-­compulsive disorder. Mol Psychiatry
2006; 11:­622–­632.
21. Fung R, et al. Retrospective review of fluvoxamine-­clomipramine combination therapy in obsessive-­compulsive disorder in children and
adolescents. J Can Acad Child Adolesc Psychiatry 2021; 30:­150–­155.
22. Hardy NE, et al. Clomipramine in combination with fluvoxamine: a potent medication combination for severe or refractory pediatric OCD.
J Can Acad Child Adolesc Psychiatry 2021; 30:­273–­277.
23. Masi G, et al. Aripiprazole augmentation in 39 adolescents with medication-­resistant obsessive-­compulsive disorder. J Clin Psychopharmacol
2010; 30:­688–­693.
24. Ardic UA, et al. Successful treatment response with aripiprazole augmentation of SSRIs in refractory ­obsessive–­compulsive disorder in childhood. Child Psychiatry Hum Dev 2017; 48:­699–­704.
25. Simeon J, et al. A retrospective chart review of risperidone use in treatment-­resistant children and adolescents with psychiatric disorders. Prog
Neuropsychopharmacol Biol Psychiatry 2002; 26:­267–­275.
26. Masi G, et al. Antipsychotic augmentation of selective serotonin reuptake inhibitors in resistant tic-­related obsessive-­compulsive disorder in
children and adolescents: a naturalistic comparative study. J Psychiatr Res 2013; 47:­1007–­1012.
27. Fineberg NA, et  al. Sustained response versus relapse: the pharmacotherapeutic goal for obsessive-­compulsive disorder. Int Clin
Psychopharmacol 2007; 22:­313–­322.
28. Fineberg NA, et al. Pharmacotherapy of obsessive-­compulsive disorder: evidence-­based treatment and beyond. Austr N Z J Psychiatry 2013;
47:­121–­141.
29. Kolevzon A, et  al. Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J Clin Psychiatry 2006;
67:­407–­414.
30. Ercan ES, et al. A promising preliminary study of aripiprazole for treatment-­resistant childhood obsessive-­compulsive disorder. J Child
Adolesc Psychopharmacol 2015; 25:­580–­584.
31. Fung R, et al. Retrospective review of fluvoxamine-­clomipramine combination therapy in obsessive-­compulsive disorder in children and
adolescents. J Can Acad Child Adolesc Psychiatry 2021; 30:­150–­155.
32. Parli GM, et al. N-­acetylcysteine for obsessive-­compulsive and related disorders in children and adolescents: a review. Ann Pharmacother
2023; 57:­847–­854.
33. Hosenbocus S, et al. Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2013;
22:­166–­171.
34. Häge A, et al. Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) –­
study protocol for a randomised controlled trial. Trials 2016; 17:141.
35. Niemeyer L, et al. Memantine as treatment for compulsivity in child and adolescent psychiatry: descriptive findings from an incompleted
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36. Naguy A, et al. Lamotrigine augmentation in treatment-­resistant pediatric obsessive-­compulsive disorder with a 16 month follow-­up. J Child
Adolesc Psychopharmacol 2016; 26:­769–­772.
37. Berlin HA, et al. Double-­blind, placebo-­controlled trial of topiramate augmentation in treatment-­resistant obsessive-­compulsive disorder.
J Clin Psychiatry 2011; 72:­716–­721.
38. Van Ameringen M, et al. Topiramate augmentation in treatment-­resistant obsessive-­compulsive disorder: a retrospective, open-­label case
series. Depress Anxiety 2006; 23:­1–­5.
39. Afshar H, et al. Topiramate augmentation in refractory obsessive-­compulsive disorder: a randomized, double-­blind, placebo-­controlled trial.
J Res Med Sci 2014; 19:­976–­981.
40. Pampaloni I, et al. High-­dose selective serotonin reuptake inhibitors in OCD: a systematic retrospective case notes survey. J Psychopharmacol
2010; 24:­1439–­1445.
41. Ninan PT, et al. High-­dose sertraline strategy for nonresponders to acute treatment for obsessive-­compulsive disorder: a multicenter double-­
blind trial. J Clin Psychiatry 2006; 67:­15–­22.
42. Rabinowitz I, et  al. High-­dose escitalopram for the treatment of ­obsessive–­compulsive disorder. Int Clin Psychopharmacol 2008;
23:­49–­53.
43. Mowla A, et  al. Duloxetine augmentation in resistant obsessive-­compulsive disorder: a double-­blind controlled clinical trial. J Clin
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44. Dougherty DD, et al. Open-­label study of duloxetine for the treatment of obsessive-­compulsive disorder. Int J Neuropsychopharmacol 2015;
18:pyu062.
45. Koran LM, et al. Mirtazapine for obsessive-­compulsive disorder: an open trial followed by double-­blind discontinuation. J Clin Psychiatry
2005; 66:­515–­520.
46. Mowla A, et  al. Pregabalin augmentation for resistant obsessive-­compulsive disorder: a double-­blind placebo-­controlled clinical trial.
CNS Spectr 2020; 25:­552–­556.
47. Eissazade N, et al. Efficacy and safety of 5-­hydroxytryptamine-­3 (5-­HT3) receptor antagonists in augmentation with selective serotonin
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48. Rodriguez CI, et al. Rapid resolution of obsessions after an infusion of intravenous ketamine in a patient with treatment-­resistant obsessive-­
compulsive disorder. J Clin Psychiatry 2011; 72:­567–­569.
49. Grant JE, et  al. Tolcapone in obsessive-­compulsive disorder: a randomized double-­blind placebo-­controlled crossover trial. Int Clin
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50. Zheng H, et al. Combined fluvoxamine and extended-­release methylphenidate improved treatment response compared to fluvoxamine
alone in patients with treatment-­refractory obsessive-­compulsive disorder: a randomized double-­blind, placebo-­controlled study.
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51. Abdelnaim MA, et al. Deep brain stimulation for treatment resistant obsessive compulsive disorder; an observational study with ten patients
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30 - Post traumatic stress disorder (PTSD) in chil
Post-traumatic stress disorder (PTSD) in children and adolescents
Prescribing in children and adolescents
CHAPTER 5
Post-­traumatic stress disorder (PTSD) in children and adolescents
Diagnostic issues
Traumatic events and PTSD are common in young people. One in three children ­experiences
traumatic events1 and about 1 in 13 children develops PTSD before age 18.1 The prevalence of PTSD in adolescents can be much higher in at-­risk groups, for example those
attending emergency departments, in forensic settings or among refugee/asylum seekers.
Young people with PTSD are at high risk of self-­harm (nearly 50%) and suicide attempt
(20%) and are often functionally impaired, for example not being in education, employment or education (NEET) (more than 25%).1 Of note, more than three out of four young
people with PTSD have comorbid psychiatric diagnoses, most commonly depression, conduct disorder, alcohol dependence or generalised anxiety disorder.1 Furthermore, PTSD is
not the most common diagnosis in trauma-­exposed young ­people –­ disorders that are
most prevalent in the general population (e.g. depression, conduct disorder, alcohol
dependence) are also more prevalent in trauma-­exposed young people.1
A diagnosis of PTSD is based on the triad of intrusive re-­experiencing, avoidance of
stimuli associated with the trauma and hyper-­arousal after trauma exposure. Because
of the abnormal processing of traumatic memories, young people with PTSD may suffer persistent re-­experiencing of the traumatic event(s) through nightmares or unwanted
and distressing memories, which are often experienced as if they were happening in the
‘here and now’ and often do not appear as frank dissociative symptoms or flashbacks.
In order to minimise re-­experiencing symptoms, young people with PTSD often develop
overt or covert avoidance strategies, keeping themselves busy or distracted or staying
away from people or places that remind them of the traumatic event. As a result of the
symptoms, young people with PTSD often feel under continued threat and, therefore,
display physiological hyper-­arousal, appearing alert and vigilant for danger, irritable
and struggling to concentrate on daily tasks. Because of the varied clinical manifestations, the assessment and treatment of PTSD in children and adolescents should be
undertaken by clinicians who have expertise in the clinical presentations seen in trauma-­
exposed children and can appreciate developmental variations in the ­manifestation of
symptoms.
Clinical guidance
The UK NICE guidelines2 advise that treatment of PTSD in young people should focus
on psychotherapy, with 12 sessions of trauma-­focused CBT (TF-­CBT) for PTSD resulting from a single traumatic event or longer for chronic or recurrent events. If TF-­CBT
is not effective, or based on the young person’s preference, treatment may also include
eye movement desensitisation and reprocessing (EMDR).
Based on the current evidence in NICE guidelines,2 the AACAP3 and the International
Society for Traumatic Stress Studies (ISTSS),4 pharmacotherapy is not recommended for
treatment of PTSD in young people. The evidence for efficacy of pharmacotherapy (SSRIs
and SGAs) in adults is also somewhat limited at present.5,6 However, because of the high
rates of comorbidity,1 pharmacotherapy may be needed to target co-­occurring psychiatric
disorders. In adult PTSD, the best supported treatments are fluoxetine, ­paroxetine and

31 - References
References

32 - Diagnostic issues
Diagnostic issues

33 - Clinical guidance
Clinical guidance
Prescribing in children and adolescents
CHAPTER 5
Post-­traumatic stress disorder (PTSD) in children and adolescents
Diagnostic issues
Traumatic events and PTSD are common in young people. One in three children ­experiences
traumatic events1 and about 1 in 13 children develops PTSD before age 18.1 The prevalence of PTSD in adolescents can be much higher in at-­risk groups, for example those
attending emergency departments, in forensic settings or among refugee/asylum seekers.
Young people with PTSD are at high risk of self-­harm (nearly 50%) and suicide attempt
(20%) and are often functionally impaired, for example not being in education, employment or education (NEET) (more than 25%).1 Of note, more than three out of four young
people with PTSD have comorbid psychiatric diagnoses, most commonly depression, conduct disorder, alcohol dependence or generalised anxiety disorder.1 Furthermore, PTSD is
not the most common diagnosis in trauma-­exposed young ­people –­ disorders that are
most prevalent in the general population (e.g. depression, conduct disorder, alcohol
dependence) are also more prevalent in trauma-­exposed young people.1
A diagnosis of PTSD is based on the triad of intrusive re-­experiencing, avoidance of
stimuli associated with the trauma and hyper-­arousal after trauma exposure. Because
of the abnormal processing of traumatic memories, young people with PTSD may suffer persistent re-­experiencing of the traumatic event(s) through nightmares or unwanted
and distressing memories, which are often experienced as if they were happening in the
‘here and now’ and often do not appear as frank dissociative symptoms or flashbacks.
In order to minimise re-­experiencing symptoms, young people with PTSD often develop
overt or covert avoidance strategies, keeping themselves busy or distracted or staying
away from people or places that remind them of the traumatic event. As a result of the
symptoms, young people with PTSD often feel under continued threat and, therefore,
display physiological hyper-­arousal, appearing alert and vigilant for danger, irritable
and struggling to concentrate on daily tasks. Because of the varied clinical manifestations, the assessment and treatment of PTSD in children and adolescents should be
undertaken by clinicians who have expertise in the clinical presentations seen in trauma-­
exposed children and can appreciate developmental variations in the ­manifestation of
symptoms.
Clinical guidance
The UK NICE guidelines2 advise that treatment of PTSD in young people should focus
on psychotherapy, with 12 sessions of trauma-­focused CBT (TF-­CBT) for PTSD resulting from a single traumatic event or longer for chronic or recurrent events. If TF-­CBT
is not effective, or based on the young person’s preference, treatment may also include
eye movement desensitisation and reprocessing (EMDR).
Based on the current evidence in NICE guidelines,2 the AACAP3 and the International
Society for Traumatic Stress Studies (ISTSS),4 pharmacotherapy is not recommended for
treatment of PTSD in young people. The evidence for efficacy of pharmacotherapy (SSRIs
and SGAs) in adults is also somewhat limited at present.5,6 However, because of the high
rates of comorbidity,1 pharmacotherapy may be needed to target co-­occurring psychiatric
disorders. In adult PTSD, the best supported treatments are fluoxetine, ­paroxetine and
596
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
venlafaxine.7 3,4-­Methylenedioxymethamphetamine (MDMA),8 ­ketamine9 and psychedelic drugs10 also show promise. Prazosin appears to be effective in reducing PTSD-­related
nightmares in children aged ­4–­18 years.11 None of these agents is currently used to any
extent in children and adolescents.
References
Lewis SJ, et al. The epidemiology of trauma and post-­traumatic stress disorder in a representative cohort of young people in England and
Wales. Lancet Psychiatry 2019; 6:­247–­256.
National Institute for Clinical Excellence. Post-­traumatic stress disorder. NICE Guideline [NG116]. 2018 (last checked December 2023);
https://www.nice.org.uk/guidance/NG116.
Cohen JA, et al. Practice parameter for the assessment and treatment of children and adolescents with posttraumatic stress disorder. J Am
Acad Child Adolesc Psychiatry 2010; 49:­414–­430.
International Society for Traumatic Stress Studies (ISTSS). Posttraumatic stress disorder prevention and treatment guidelines: methodology
and recommendations. 2019; https://istss.org/getattachment/Treating-­Trauma/New-­ISTSS-­Prevention-­and-­Treatment-­Guidelines/ISTSS_
PreventionTreatmentGuidelines_FNL-­March-­19-­2019.pdf.aspx.
Cipriani A, et al. Comparative efficacy and acceptability of pharmacological treatments for post-­traumatic stress disorder in adults: a network meta-­analysis. Psychol Med 2018; 48:­1975–­1984.
Huang ZD, et al. Comparative efficacy and acceptability of pharmaceutical management for adults with post-­traumatic stress disorder: a
systematic review and meta-­analysis. Front Pharmacol 2020; 11:559.
Ehret M. Treatment of posttraumatic stress disorder: focus on pharmacotherapy. Ment Health Clin 2019; 9:­373–­382.
Jerome L, et al. Long-­term follow-­up outcomes of MDMA-­assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of
six phase 2 trials. Psychopharmacology (Berl) 2020; 237:­2485–­2497.
Fremont R, et al. Ketamine for treatment of posttraumatic stress disorder: state of the field. Focus (Am Psychiatr Publ) 2023; 21:­257–­265.
Krediet E, et al. Reviewing the potential of psychedelics for the treatment of PTSD. Int J Neuropsychopharmacol 2020; 23:­385–­400.
Hudson N, et al. Evaluation of low dose prazosin for PTSD-­associated nightmares in children and adolescents. Ment Health Clin 2021;
11:­45–­49.

34 - Attention deficit hyperactivity disorder (ADH
Attention deficit hyperactivity disorder (ADHD) in children and adolescents
Prescribing in children and adolescents
CHAPTER 5
Attention deficit hyperactivity disorder (ADHD) in children and
adolescents
■
■A diagnosis of ADHD should be made only after a comprehensive assessment by a
specialist with expertise in ADHD.1 Appropriate psychological, psychosocial and
behavioural interventions should be put in place. Drug treatments should be only a
part of the overall treatment plan.
■
■The indication for drug treatment is the presence of impairment resulting from
ADHD despite environmental modifications, parent training (if appropriate), advice
on parenting strategies and liaison with school.
■
■Methylphenidate is the first-­line treatment when medication is indicated. It is a central
nervous system (CNS) stimulant with a large evidence base from trials. Most common
adverse effects include insomnia, appetite suppression, raised blood pressure, raised
pulse rate and growth deceleration. These adverse effects can usually be managed by
treatment breaks or dose reduction, depending on the side effect. Long-­term use in
children is associated with lower height and weight.2 In the UK and elsewhere, there
are several modified-release preparations with different release profiles available,
including generic options.
■
■Dexamfetamine is an alternative CNS stimulant. Effects and adverse reactions are
broadly similar to methylphenidate, but there is somewhat less evidence for efficacy and safety than exists for methylphenidate. Dexamfetamine is probably more
likely to be diverted and misused. Both methylphenidate and dexamfetamine are
Controlled Drugs in most countries. This makes prescribing and dispensing more
complex.
■
■Lisdexamfetamine is a pro-­drug –­ dexamfetamine is complexed with the amino acid
lysine and in this form is inactive. It is broken down in red blood cells so that
­dexamfetamine is gradually made available. It therefore has a similar practical role to
extended-­release preparations of methylphenidate and, like them, is unlikely to be
abused for recreational or dependency-­driven purposes. Several RCTs have established it as superior to placebo in children3,4 and adolescents.5 Effect size from preliminary research appears to be at least as great as that of osmotic-controlled release
oral delivery system (OROS)-­methylphenidate4 and it seems to have a similar range
of adverse effects.6,7 Network meta-­analyses found lisdexamfetamine to be more
effective than methylphenidate8,9 and long-­term data suggest that it can be considered
as an alternative to extended-­release methylphenidate.10 Lisdexamfetamine is also
effective in pre-­school children11 although it is not licensed for this age group.
■
■Atomoxetine is a non-­stimulant alternative.­12–­15 It may be particularly useful for children who do not respond to stimulants, where stimulant diversion is a problem or
when ‘dopaminergic’ adverse effects (such as tics, anxiety and stereotypies) become
problematic on stimulants. Parents should be warned of the possibilities of suicidal
thinking and emerging liver disease and advised of the possible features that they
might notice. Atomexetine is less effective than stimulants.9,13,16,17
598
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
■
■A licensed modified-­release preparation of guanfacine is approved in the UK and elsewhere for use in children with ADHD. Guanfacine is an α2 agonist medication and can
be considered as an alternative non-­stimulant medication to atomoxetine.18 It is
broadly as effective as atomoxetine.19 Although not licensed for adults in most countries, children started on guanfacine should probably continue as adults.
■
■Another non-­stimulant medication with evidence of effectiveness in the treatment for
ADHD is the α2 agonist clonidine.20 Extended-­release clonidine is widely used for
ADHD in the USA but not licensed in most countries.
■
■There is some evidence supporting the efficacy of tricyclic antidepressants21,22 but
these are not recommended in clinical practice.
■
■Bupropion9,23,24 seems to be efficacious and well tolerated. Modafinil also appears to
have useful activity in children but not in adults with ADHD.9,25,26 Evidence supporting the use of these drugs is somewhat limited compared with standard treatments.9
Viloxazine is also effective27 and approved in the USA.
■
■The use of second-­generation antipsychotics28,29 for ADHD is not recommended.28,29
These may reduce hyperactivity in autism spectrum disorders30 but should not be
prescribed for this indication.
■
■Emerging ADHD pharmacotherapies31 include the SNRIs venlafaxine and ­duloxetine,
agomelatine, dasotraline (a serotonin, noradrenaline and dopamine reuptake inhibitor) and tipepidine (potassium channel inhibitor).
■
■Comorbid psychiatric illness is common in children with ADHD. Stimulants are often
helpful overall but are unlikely to be appropriate for children who have a psychotic
illness. Problems with substance misuse should be managed in their own right
­alongside ADHD treatment32 and treatments need to be chosen carefully.
■
■Combinations of stimulants and atomoxetine have been used, but there are few trials
and no clear evidence for improved efficacy.33
■
■Combinations of stimulants and guanfacine are approved in some countries. There
is  some evidence that the combination might have additive effects on symptoms
control.34
■
■Once stimulant treatment has been established, it is appropriate for repeat prescriptions to be supplied through general practitioners1 with reviews at least once a year
by a healthcare professional with training and expertise in managing ADHD.
Box  5.1 summarises the NICE guidelines for treating children with ADHD and
Table 5.10 summarises prescribing in ADHD.
Prescribing in children and adolescents
CHAPTER 5
Box 5.1  Summary of UK NICE guidance for ADHD in children1
■
■Drug treatment should only be initiated by a specialist and only after comprehensive assessment
of mental and physical health and social influences. In children under 5 years, medication should
be initiated after a second specialist opinion from an ADHD service with expertise in managing
ADHD in younger children (ideally a tertiary service)
■
■An ADHD-­focused group parent-­training programme should be offered for parents or carers of
children aged less than 5 years with ADHD. Environmental modifications need to be implemented in all cases. If ADHD symptoms are still causing a persistent significant impairment in at
least one domain despite environmental modifications, medication can be offered following a
baseline assessment
■
■Methylphenidate, lisdexamfetamine, dexamfetamine, atomoxetine and guanfacine are recommended within their licensed indications
■
■Methylphenidate (either short or long acting) is the first choice of medication
■
■Consider switching to lisdexamfetamine for children aged 5 years and over and young people
who have had a 6-­week trial of methylphenidate at an adequate dose and not derived enough
benefit in terms of reduced ADHD symptoms and associated impairment
■
■Consider dexamfetamine for children aged 5 years and over and young people whose ADHD
symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect
profile
■
■Offer atomoxetine or guanfacine to children aged 5 years and over and young people if they
cannot tolerate methylphenidate or lisdexamfetamine or their symptoms have not responded to
separate 6-­week trials of lisdexamfetamine and methylphenidate, having considered alternative
preparations and adequate doses
■
■Monitoring should include measurement of height and weight (with entry on growth charts)
and recording of blood pressure and heart rate. An electrocardiogram is not needed before
starting stimulants* atomoxetine or guanfacine unless the person has any of the following:
■
■History of congenital heart disease or previous cardiac surgery
■
■history of sudden death in a first-­degree relative under 40 years suggesting a cardiac disease
■
■shortness of breath on exertion compared with peers
■
■fainting on exertion or in response to fright or noise
■
■palpitations that are rapid, regular and start and stop suddenly
■
■chest pain suggesting cardiac origin
■
■signs of heart failure
■
■a murmur heard on cardiac examination
■
■blood pressure that is classified as hypertensive for adults
■
■a coexisting condition that is being treated with a medicine that may pose an increased
cardiac risk
A cardiology opinion should be sought if any of the above apply
*The cardiovascular toxicity of stimulants remains poorly quantified. Some analyses show no adverse effect35
while population studies suggest increased risk of hypertension and other adverse outcomes.36
CHAPTER 5
Table 5.10  Prescribing in attention deficit hyperactivity disorder (ADHD).
Medication
Onset and
duration of
action
Dose
Notes
Recommended
monitoring/general
notes
Methylphenidate
immediate release
Branded products
(Ritalin, Medikinet,
Tranquilyn) and
various generic
preparations
­available­­37–39
Onset:
­20–­60 minutes
Duration: ­2–­4
hours
Initially ­5–­10mg daily
titrated up in weekly
increments of ­5–­10mg,
to a maximum of 2.1mg/
kg/day in divided doses.
Licensed maximum dose
60mg daily (or after
specialist review up to
90mg daily)1
Methylphenidate usually
first-­line treatment in
ADHD. Generally well
tolerated40
For methylphenidate,
dexamfetamine and
lisdexamfetamine
Monitor:
■
■Blood pressure41
■
■Pulse
■
■Height
■
■Weight
Monitor for insomnia,
mood and appetite
change and the
development of tics,42
although some
evidence suggests tics
are not associated with
psychostimulants43
Discontinue if no
benefits seen in
1 month
Controlled Drugs
Methylphenidate
modified release*
An afternoon dose of
immediate-release
methylphenidate may be
necessary in some
children to optimise
treatment.
Concerta XL37,38,­44–­46
Bioequivalent
versions: Affenid XL,
Xaggitin XL,
Matoride XL,
Xenidate XL,
Delmosart modified
release
Onset:
0.5 –­2 hours
Duration:
12 hours
Initially 18mg in the
morning, titrated up to a
licensed maximum dose
of 54mg daily (or after
specialist review up to
108mg daily; NB
unlicensed)
18mg = 15mg
methylphenidate
immediate release
Consists of an
immediate-­release
component (22% of the
dose) and a modified-­
release component (78%
of the dose).
Equasym XL47,48
Onset:
­20–­60 minutes
Duration: 8
hours
Initially 10mg in the
morning, titrated up to a
licensed maximum dose
of 60mg daily
Consists of an immediate-­
release component (30%
of the dose) and a
modified-­release
component (70% of the
dose). Capsules can be
opened and sprinkled.
Medikinet XL
Bioequivalent
versions: Metyrol XL
and Meflynate
Onset:
­20–­60 minutes
Duration: up
to 8 hours
Dose as for Equasym XL
Consists of an immediate-­
release component (50%
of the dose) and a
modified-­release
component (50% of the
dose). Capsules can be
opened and sprinkled.49
Table 5.10  (Continued)
Onset and
duration of
action
Dose
Notes
Medication
Ritalin XL50
Onset:
60 minutes
Duration:
8–­12 hours
Dexamfetamine
immediate
release40,51
Initially 2.­5–­10mg daily,
titrated up in weekly
increments of 2.­5–­5mg,
to a maximum of 20mg
daily in divided doses
(occasionally up to 40mg
daily is necessary)
Onset:
­20–­60 minutes
Duration: ­3–­6
hours
Lisdexamfetamine
(Elvanse)­3–­5
Onset:
­20–­60 minutes
Duration: 13+
hours
Initially 20 or 30mg in
the morning, titrated up
to a licensed maximum
dose of 70mg daily
Atomoxetine53,54
Approximately
­4–­6 weeks
(atomoxetine is
a noradrenaline
reuptake
inhibitor)
When switching from a
stimulant, continue
stimulant for first
4 weeks of therapy.
For children <70kg:
Initially 0.5mg/kg/day for
7 days, then increase
according to response.
Recommended
maintenance dose
1.2mg/kg/day (in single
or divided doses) and up
to 1.8mg/kg/day, to a
maximum of 120mg
daily if necessary1
For children >70kg:
Initially 40mg daily for
7 days, then increase
according to response.
Recommended
maintenance dose
80mg daily
Prescribing in children and adolescents
Recommended
monitoring/general
notes
Dose as for Equasym XL
Consists of an
immediate-­release
component (50% of the
dose) and a modified-­
release component (50%
of the dose).
Considered to be less
well tolerated than
methylphenidate.40
Pro-drug, gradually
hydrolysed to
dexamfetamine
Capsules can be opened
and sprinkled.52
Licensed in adults
CHAPTER 5
Less effective than
stimulants (see text).13,17
Monitor:
■
■Blood pressure56
■
■Pulse
May be useful where
stimulant diversion is a
problem.55
■
■Height
■
■Weight
Monitor for insomnia,
mood and appetite
change and the
development of tics.
Licensed in adults
Monitor young people
and adults with ADHD
for sexual dysfunction
(that is, erectile and
ejaculatory
dysfunction) as
potential adverse
effects of
atomoxetine.
Not a Controlled Drug
(Continued )
602
The Maudsley® Prescribing Guidelines in Psychiatry
Table 5.10  (Continued)
Onset and
duration of
action
Dose
Notes
Medication
Guanfacine
modified release9,57
Approximately
­1–­ 5 weeks58
(guanfacine is
a central
alpha2Aadrenergic
receptor
agonist)
For child ­6–­12 years
(body weight 25kg
and above):
Initially 1mg once daily;
adjusted in steps of 1mg
every week if necessary
and if tolerated;
maintenance
0.­05–­0.12mg/kg once
daily (max. per dose 4mg)
For child ­13–­17 years
(body weight
­34–­41.4kg):
Initially 1mg once daily;
adjusted in steps of 1mg
every week if necessary
and if tolerated;
maintenance
0.­05–­0.12mg/kg once
daily (max. per dose 4mg)
For child ­13–­17 years
(body weight
41.­5–­49.4kg):
Initially 1mg once daily;
adjusted in steps of 1mg
every week if necessary
and if tolerated;
maintenance
0.­05–­0.12mg/kg once
daily (max. per dose 5mg)
CHAPTER 5
For child ­13–­17 years
(body weight
49.­5–­58.4kg):
Initially 1mg once daily;
adjusted in steps of 1mg
every week if necessary
and if tolerated;
maintenance
0.­05–­0.12mg/kg once
daily (max. per dose 6mg)
For child ­13–­17 years
(body weight 58.5kg
and above):
Initially 1mg once daily;
adjusted in steps of 1mg
every week if necessary
and if tolerated;
maintenance
0.­05–­0.12mg/kg once
daily (max. per dose 7mg)
*For details of other preparations available outside the UK, see Cortese et al., 2017.59
Recommended
monitoring/general
notes
Efficacy and tolerability
data should be
interpreted with
caution.9
Similar monitoring to
other medication for
ADHD.

35 - References
References
Prescribing in children and adolescents
CHAPTER 5
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Biederman J, et al. Lisdexamfetamine dimesylate and mixed amphetamine salts extended-­release in children with ADHD: a double-­blind,
placebo-­controlled, crossover analog classroom study. Biol Psychiatry 2007; 62:­970–­976.
Coghill D, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-­deficit/
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Findling RL, et al. Efficacy and safety of lisdexamfetamine dimesylate in adolescents with attention-­deficit/hyperactivity disorder. J Am Acad
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Heal DJ, et al. Amphetamine, past and ­present –­ a pharmacological and clinical perspective. J Psychopharmacol 2013; 27:­479–­496.
Coghill DR, et al. Long-­term safety and efficacy of lisdexamfetamine dimesylate in children and adolescents with ADHD: a phase IV, 2-­year,
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Joseph A, et al. Comparative efficacy and safety of attention-­deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended
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Cortese S, et al. Comparative efficacy and tolerability of medications for attention-­deficit hyperactivity disorder in children, adolescents, and
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Findling RL, et  al. Long-­term effectiveness and safety of lisdexamfetamine dimesylate in school-­aged children with attention-­deficit/­
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Childress AC, et al. Efficacy and safety of lisdexamfetamine in preschool children with attention-­deficit/hyperactivity disorder. J Am Acad
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Michelson D, et al. Once-­daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a ­randomized,
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Kratochvil CJ, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-­label trial.
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Weiss M, et al. A randomized, placebo-­controlled study of once-­daily atomoxetine in the school setting in children with ADHD. J Am Acad
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Kratochvil CJ, et al. A double-­blind, placebo-­controlled study of atomoxetine in young children with ADHD. Pediatrics 2011; 127:­e862–­e868.
Catala-­Lopez F, et al. The pharmacological and non-­pharmacological treatment of attention deficit hyperactivity disorder in children and
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Connor DF, et al. A meta-­analysis of clonidine for symptoms of attention-­deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry
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Hazell P. Tricyclic antidepressants in children: is there a rationale for use? CNS Drugs 1996; 5:­233–­239.
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Gorman DA, et al. Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with
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Ng QX. A systematic review of the use of bupropion for attention-­deficit/hyperactivity disorder in children and adolescents. J Child Adolesc
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Biederman J, et al. A comparison of once-­daily and divided doses of modafinil in children with attention-­deficit/hyperactivity disorder: a
randomized, double-­blind, and placebo-­controlled study. J Clin Psychiatry 2006; 67:­727–­735.
Wang SM, et al. Modafinil for the treatment of attention-­deficit/hyperactivity disorder: a meta-­analysis. J Psychiatr Res 2017; 84:­292–­300.
Nasser A, et al. A phase III, randomized, double-­blind, placebo-­controlled trial assessing the efficacy and safety of viloxazine extended-­release
capsules in adults with attention-­deficit/hyperactivity disorder. CNS Drugs 2022; 36:­897–­915.
Einarson TR, et al. Novel Antipsychotics for Patients with Attention-­Deficit Hyperactivity Disorder: a Systematic Review. Technology Report
No. 17. Ottawa: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); 2001.
Pringsheim T, et al. The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-­deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-­analysis.
Part 2: antipsychotics and traditional mood stabilizers. Can J Psychiatry 2015; 60:­52–­61.
Ji N, et  al. An update on pharmacotherapy for autism spectrum disorder in children and adolescents. Curr Opin Psychiatry 2015;
28:­91–­101.
Pozzi M, et al. Emerging drugs for the treatment of attention-­deficit hyperactivity disorder (ADHD). Expert Opin Emerg Drugs 2020;
25:­395–­407.
Humphreys KL, et al. Stimulant medication and substance use outcomes: a meta-­analysis. JAMA Psychiatry 2013; 70:­740–­749.
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33. Treuer T, et al. A systematic review of combination therapy with stimulants and atomoxetine for attention-­deficit/hyperactivity disorder,
including patient characteristics, treatment strategies, effectiveness, and tolerability. J Child Adolesc Psychopharmacol 2013; 23:­179–­193.
34. McCracken JT, et al. Combined stimulant and guanfacine administration in attention-­deficit/hyperactivity disorder: a controlled, comparative study. J Am Acad Child Adolesc Psychiatry 2016; 55:­657–­666.e651.
35. Zhang L, et al. Risk of cardiovascular diseases associated with medications used in attention-­deficit/hyperactivity disorder: a systematic
review and meta-­analysis. JAMA Network Open 2022; 5:e2243597.
36. Zhang L, et al. Attention-­deficit/hyperactivity disorder medications and long-­term risk of cardiovascular diseases. JAMA Psychiatry 2024;
81:­178–­187.
37. Wolraich ML, et al. Pharmacokinetic considerations in the treatment of attention-­deficit hyperactivity disorder with methylphenidate. CNS
Drugs 2004; 18:­243–­250.
38. Joint Formulary Committee. British National Formulary (online). London: BMJ and Pharmaceutical Press; http://www.medicinescomplete.com.
39. Janssen-­Cilag Ltd. Summary of product characteristics. Concerta XL 18mg, 27mg, 36mg and 54mg prolonged-­release tablets. 2023;
https://www.medicines.org.uk/emc/product/6872/smpc.
40. Efron D, et al. Side effects of methylphenidate and dexamphetamine in children with attention deficit hyperactivity disorder: a double-­blind,
crossover trial. Pediatrics 1997; 100:­662–­666.
41. Hennissen L, et al. Cardiovascular effects of stimulant and non-­stimulant medication for children and adolescents with ADHD: a systematic
review and meta-­analysis of trials of methylphenidate, amphetamines and atomoxetine. CNS Drugs 2017; 31:­199–­215.
42. Gadow KD, et al. Efficacy of methylphenidate for attention-­deficit hyperactivity disorder in children with tic disorder. Arch Gen Psychiatry
1995; 52:­444–­455.
43. Cohen SC, et al. Meta-­analysis: risk of tics associated with psychostimulant use in randomized, placebo-­controlled trials. J Am Acad Child
Adolesc Psychiatry 2015; 54:­728–­736.
44. Hoare P, et al. 12-­month efficacy and safety of OROS MPH in children and adolescents with attention-­deficit/hyperactivity disorder switched
from MPH. Eur Child Adolesc Psychiatry 2005; 14:­305–­309.
45. Remschmidt H, et al. Symptom control in children and adolescents with attention-­deficit/hyperactivity disorder on switching from immediate-­
release MPH to OROS MPH. Results of a 3-­week open-­label study. Eur Child Adolesc Psychiatry 2005; 14:­297–­304.
46. Wolraich ML, et al. Randomized, controlled trial of OROS methylphenidate once a day in children with attention-­deficit/hyperactivity disorder. Pediatrics 2001; 108:­883–­892.
47. Findling RL, et al. Comparison of the clinical efficacy of twice-­daily Ritalin and once-­daily Equasym XL with placebo in children with attention deficit/hyperactivity disorder. Eur Child Adolesc Psychiatry 2006; 15:­450–­459.
48. Anderson VR, et al. Spotlight on methylphenidate controlled-­delivery capsules (Equasym XLTM) in the treatment of children and adolescents
with attention-­deficit hyperactivity disorder. CNS Drugs 2007; 21:­173–­175.
49. Flynn Pharma Ltd. Summary of product characteristics. Medikinet XL 5mg, 10mg, 20mg, 30mg, 40mg, 50mg and 60mg modified release
capsules (methylphenidate hydrochloride). 2023; https://www.medicines.org.uk/emc/product/313/smpc.
50. Medicines and Healthcare products Regulatory Agency. Public assessment report. Ritalin XL 10mg, 20mg, 30mg, 40mg, 60mg modified-­
release hard capsules (last updated March 2014); https://mhraproductsproduction.blob.core.windows.net/docs/4781baf366b1fafd0ea20396
2ccb54faadcdcfcc.
51. Cyr M, et al. Current drug therapy recommendations for the treatment of attention deficit hyperactivity disorder. Drugs 1998; 56:­215–­223.
52. Takeda UK Ltd. Summary of product characteristics. Elvanse 20mg, 30mg, 40mg, 50mg, 60mg and 70mg capsules, hard (lisdexafetamine).
2023; https://www.medicines.org.uk/emc/product/14091/smpc.
53. Kelsey DK, et al. Once-­daily atomoxetine treatment for children with attention-­deficit/hyperactivity disorder, including an assessment of
evening and morning behavior: a double-­blind, placebo-­controlled trial. Pediatrics 2004; 114:­e1–­e8.
54. Wernicke JF, et al. Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf 2003; 26:­729–­740.
55. Heil SH, et al. Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users.
Drug Alcohol Depend 2002; 67:­149–­156.
56. Reed VA, et al. The safety of atomoxetine for the treatment of children and adolescents with attention-­deficit/hyperactivity disorder: a comprehensive review of over a decade of research. CNS Drugs 2016; 30:­603–­628.
57. Childress A, et al. Evaluation of the current data on guanfacine extended release for the treatment of ADHD in children and adolescents.
Expert Opin Pharmacother 2020; 21:­417–­426.
58. Takeda UK Ltd. Guanfacine modified-­release. Personal communication, 2020.
59. Cortese S, et al. New formulations of methylphenidate for the treatment of attention-­deficit/hyperactivity disorder: pharmacokinetics, efficacy, and tolerability. CNS Drugs 2017; 31:­149–­160.

36 - Autism spectrum disorder (ASD) in children an
Autism spectrum disorder (ASD) in children and adolescents

37 - Pharmacological treatment of core ASD symptom
Pharmacological treatment of core ASD symptoms
Prescribing in children and adolescents
CHAPTER 5
Autism spectrum disorder (ASD) in children and adolescents
Autism spectrum disorder is a complex condition characterised by core deficits in social
communication development and behaviour (stereotypies and/or restricted and unusual patterns of interests) as well as sensory difficulties. ICD-­11 now matches DSM-­5 in
removing the subtypes of autism (e.g. the term Asperger’s syndrome has been discontinued). In addition, ICD-­11 distinguishes between ASD with or without intellectual
development. DSM-­5 recommends recording whether or not there is accompanying
intellectual impairment.
The heterogeneity of ASD poses assessment and treatment challenges. Co-­occurring
mental health conditions are highly prevalent in ASD1 with ­69–­79% of individuals
experiencing at least one in their lifetime.2,3 These include attention deficit hyperactivity
disorder (ADHD), disruptive behavioural disorders, anxiety and obsessive compulsive
and mood disorders. Other associated problems include intellectual disability, epilepsy,
sleep disturbance, self-­harm, irritability and aggression towards others. Associated neurodevelopmental, medical and psychiatric disorders complicate the symptom profile
and affect overall outcome. Evaluating and optimally treating co-­occurring conditions
and/or associated problem behaviours are, therefore, essential.
Currently there are no validated or licensed pharmacological treatments that alleviate core ASD symptoms.4,5 Targeting problem behaviours and comorbid psychiatric
conditions with pharmacological interventions is, however, common practice.
Pharmacotherapies are commonly used in individuals with ASD as adjuncts to psychological interventions. The evidence to date4,6 shows reasonable efficacy of risperidone and aripiprazole for irritability and aggression; supports the use of methylphenidate,
atomoxetine and guanfacine for ADHD and melatonin for sleep problems; but shows
limited efficacy of SSRIs for anxiety, depression and repetitive behaviours. The evidence for antiepileptics remains inconsistent. There is a potential role for α2 agonists,
cholinergic agonists, glutamatergic agents, gamma-­aminobutyric acid (GABA) agonists
and oxytocin but these require further investigation.4,6
Individuals with ASD are likely to experience more severe adverse effects than typically developing individuals.­4–­6 Therefore, achieving an effective dose with minimum
adverse effects can be a challenging task. Treatment should be initiated in small doses
and increased about every five half-­lives of the drug, and it may take ­4–­6 weeks of
titration to determine the therapeutic dose for each individual case.7 Excluding any
medical conditions, the presence of pain or any other physical discomfort such as
gastro-­esophageal reflux must be a priority before managing problem behaviour with
psychotropic drugs. A comprehensive physical examination should be part of standard
practice.
The efficacy and adverse effects associated with pharmacotherapy in individuals with
ASD should be systematically monitored in view of their impaired communication and
the increased propensity for more adverse effects. Standardised behaviour rating scales
and adverse effect checklists are essential tools in monitoring progress.8
Pharmacological treatment of core ASD symptoms
Evidence from clinical trials to date has not demonstrated clear efficacy of any psychotropic agent in routinely treating core symptoms of ASD.4,6
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Restricted repetitive behaviours and interests (RRBIs)
RRBIs are distressing and disruptive to functioning and therefore an important treatment target to improve overall outcomes in ASD.9 Behavioural therapies should be used
as first line. When RRBIs are severe with significant impact on functioning and/or pose
risks to others or self then pharmacotherapy can be considered.
A Cochrane review (last updated in 2013) found ‘no evidence of effect of SSRIs on
reducing RRBIs in children and emerging evidence of harm’ although there are data
that support their use in adults.10 A 2022 meta-­analysis of 16 studies demonstrated
a small effect size for antidepressants in treating restricted and repetitive behaviours. Subgroup analyses indicated that clomipramine had a higher efficacy than
SSRIs and adults had a better response than adolescents and children.11 Risperidone
is probably effective in reducing RRBIs in children who have high levels of irritability or aggression12 (any specific efficacy for repetitive behaviours is doubtful).
Reductions in stereotypical behaviours have also been ­reported­­13–16 albeit in studies
with methodological limitations.6 A 2020 meta-­analysis of studies on a wide range
of currently available pharmacological agents showed evidence supporting only
antipsychotic medication,17 whereas another recent meta-­analysis of nine studies
found no evidence for any pharmacological agent in reducing RRBIs.18 Overall,
given the profile of adverse effects of dopamine-­blocking agents, consensus guidance from the British Association for Psychopharmacology6 rightly cautions against
their routine use for the treatment of RRBIs. If they are used, they should be
­prescribed in small doses and as part of a carefully considered, time-­limited and
monitored overall treatment plan.
Social and communication impairment
Currently, no drug has been consistently shown to improve the core social and
communication impairments in ASD.7 Risperidone may have a secondary effect
through improvement in irritability.19 Analysis of data from two multicentre trials
suggested that risperidone was effective for the treatment of social disability in
children with ASD.20 Glutamatergic drugs and oxytocin looked promising.21
However, two meta-­analyses and two recent double-­blind placebo-­controlled trials
suggested that oxytocin has no significant effect on social communication.­22–­25
Larger studies with better methodology are needed.23,26 Sulforaphane has shown
mixed results with both positive and negative trials.­27–­29 Insulin growth factor 1
(IGF-1)30 awaits further work to prove its efficacy in modifying ASD core symptoms, as do glutamatergic agents.­31–­33 Acetylcysteine34 is probably not effective.
Three small double-­blind placebo-­controlled trials using folinic acid for language
impairment look encouraging.35
There is growing but inconsistent evidence for dietary interventions reducing ASD
core symptoms.36,37 The targeting of the gut microbiome, including probiotic treatment
and faecal microbiota transplants, has drawn much interest.38 However, there is little
evidence to support the use of nutritional supplements or dietary therapies for children
with ASD36 or indeed any relationship between maternal food intake and child’s diet
and the development of ASD/symptoms severity.37

38 - Pharmacological treatment of co occurring dis
Pharmacological treatment of co-occurring disorders and problem behaviours in ASD
Prescribing in children and adolescents
CHAPTER 5
Pharmacological treatment of co-­occurring disorders and problem
behaviours in ASD
Inattention, overactivity and impulsiveness in ASD (symptoms of ADHD)
Individuals with ASD have high rates of inattention, overactivity and impulsiveness and
in around a third of patients these symptoms merit the diagnosis of ADHD.1,39
The largest controlled trial to date has been with methylphenidate, conducted by the
Research Units on Paediatric Psychopharmacology (RUPP) Autism Network.40,41 In a
previous retrospective and prospective study of children with ASD, Santosh and colleagues42 reported positive benefits of treatment with methylphenidate. In general,
methylphenidate produces highly variable responses in children with ASD and ADHD
symptoms, ranging from marked improvement with few adverse effects to poor
response with or without problematic adverse effects. A large double-­blind placebo-­
controlled trial of methylphenidate in children with intellectual disability and ADHD
showed that optimal dosing with methylphenidate was effective in some.43 Adverse
effects are more commonly reported than in children with ADHD alone.­44–­46 However,
where ADHD symptoms are severe and/or disabling, it is reasonable to proceed with a
treatment trial of methylphenidate. It is advisable to warn parents of the lower likelihood of response and the potential adverse effects and to proceed with low initial doses
(around 0.125mg/kg three times daily, depending on the preparation) increasing by
small increments. Treatment should be stopped immediately if behaviour deteriorates
or there are unacceptable adverse effects. A systematic review6 confirms that, although
effective, the efficacy of methylphenidate for treatment of ADHD in ASD is less than in
ADHD alone and that more adverse effects (decreased appetite, sleeping difficulties,
abdominal discomfort, social withdrawal, irritability and emotional outbursts) should
be expected in ASD. A 2021 meta-­analysis supports the efficacy of methylphenidate
and atomoxetine.47
There are no published data on the efficacy of amfetamines in children with ASD
even though they have been used to treat ADHD in these patients as well as in typically
developed children. Lisdexamfetamine (a pro-­drug containing d-­amfetamine bound to
amino acid lysine) has been found to have efficacy and tolerability in treating ADHD in
children and young people48 but with no specific data about those with ASD.
Atomoxetine is a noradrenergic reuptake inhibitor licensed to treat ADHD with similar efficacy to methylphenidate.6 Preliminary evidence from small open-­label trials and
a handful of randomised double-­blind trials49,50 showed that it may be useful in children
with ASD, with the most common adverse effects being nausea, fatigue and sleep difficulties. These studies were followed by a larger trial that confirmed that atomoxetine
(alone and combined with parent training) significantly reduced ADHD symptoms.51 In
a 24-­week extension of the same study, atomoxetine combined with parent training
was superior in reducing ADHD symptoms to atomoxetine alone.52
There is evidence that α2 agonists (clonidine and guanfacine) can be used as alternative treatments. A multisite RCT of extended-­release guanfacine compared with placebo
in children with ASD (mean age 8.5 years) over a period of 8 weeks showed that it is
safe and effective in managing hyperactivity in this group.53 No serious adverse events
except for drowsiness, fatigue and decreased appetite were reported.
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CHAPTER 5
There are reports from controlled studies supporting the use of risperidone or
­aripiprazole for ADHD symptoms. However, these were not primary outcomes of the
studies and therefore need further investigation.
Irritability (aggression, self-­injurious behaviour, severe disruptive behaviours)
Aggression towards others and self, frequently underlined by irritability, is a common
problem in ASD. Although behavioural and environmental approaches should be first-­
line treatments, more severe and dangerous behaviours usually necessitate pharmacotherapy.54 The duration of recommended treatment is difficult to derive from published
evidence but treatment appears to be beneficial for up to ­6–­12 months.55 Efforts to
reduce and possibly discontinue such treatment at the end of this period should be
strongly considered.54,55
SGAs are the first-­line pharmacological treatment for children and adolescents with
ASD and associated irritability.­55–­58 Risperidone59,60 and aripiprazole61 have been reliably
shown to help with irritability and associated disruptive behaviours5 in ASD and have been
approved for this use by the US FDA. In a meta-­analysis of data from 46 RCTs62 comparing
efficacy of risperidone, aripiprazole and other compounds with placebo, risperidone and
aripiprazole were the most effective, with moderate to large effect sizes. Another meta-­
analysis of short-­term (8 weeks) aripiprazole in the treatment of irritability in ASD children
aged ­6–­17 years63 found similar results when compared with placebo. The most recent
Cochrane review64 concluded that aripiprazole and risperidone probably reduce both irritability and self-­injury with a large effect size. However, no effect was shown for aggression. The usual recommended dose of aripiprazole for maintenance is between 5 and 15mg
daily.55 The starting dose is 2mg/day. The dosing of risperidone is rather more ­complicated –­
FDA-recommended dosages for risperidone are outlined in Box 5.2.
Despite their promising efficacy, adverse effects such as weight gain and metabolic
changes, increased appetite and somnolence (even with aripiprazole) can be
problematic.16,­65–­68 Research is underway to determine if therapeutic drug monitoring of
risperidone and aripiprazole will help in optimising treatment while minimising weight
gain.69 One long-­term placebo discontinuation study found that relapse rates did not
differ between those who stayed on aripiprazole versus those randomised to switch to
only placebo, suggesting that re-­evaluation of aripiprazole use after a period of stabilisation in irritability symptoms is warranted.70 There is only one study that makes a direct
head-­to-­head comparison71 showing similar tolerability and efficacy profiles for risperidone and aripiprazole. Risperidone usually causes hyperprolactinaemia which, although
it may be asymptomatic, may have longer-term effects, therefore necessitating close
monitoring. Aripiprazole has no effect on prolactin, which makes it a preferred option.
Aripiprazole may on the other hand be ineffective for self-­injurious behaviours.6
Lurasidone, in fixed doses of 20 or 60mg/day, has been shown to be ineffective in a
randomised double-­blind trial over 6 weeks.72 The effectiveness of other SGAs such as
olanzapine,73 quetiapine, ziprasidone and clozapine has not been tested in adequately
powered RCTs. While controlled studies support the use of mood stabilisers such as
lithium74,75 and sodium valproate76 in the treatment of persistent aggression in children
they are not as effective as SGAs for the treatment of irritability in ASD.77 Limited data
support the combination of risperidone and topiramate being better than risperidone
alone.78 Further RCTs are probably warranted of brain-­derived neurotrophic factor
stimulators such as loxapine and amitriptyline.79
Prescribing in children and adolescents
CHAPTER 5
Use of risperidone in children and adolescents
Box 5.2  US Food and Drug Administration guidance for risperidone dosing in children and
adolescents80
■
■Risperidone is indicated for the treatment of irritability associated with autistic spectrum disorder
(ASD) in children (aged 5 years and over) and adolescents in the UK/EU and USA
■
■The dosage of risperidone should be individualised according to the response of the patient
Doses of risperidone in paediatric patients with autism spectrum disorders (by total mg/day)
Weight
categories
Days ­1–­3
Days ­4–­18
Increments if dose increases are needed
Dose range
<20kg*
0.25mg
0.5mg
+0.25mg
at ≥2-­week intervals
0.­5–­3mg†
≥20kg
0.5mg
1.0mg
+0.5mg
at ≥2-­week intervals
1.­0–­3mg‡
*Caution should be exercised for children <­15kg –­ no dosing data available
†Therapeutic effect plateaus at 1mg/day
‡Those weighing >45kg may require higher ­doses –­ therapeutic effect plateaus at 3mg
General considerations
■
■Risperidone can be administered once daily or twice daily
■
■Patients experiencing somnolence may benefit from taking the whole daily dose at bedtime
■
■Once sufficient clinical response has been achieved and maintained, consideration may be given
to gradually lowering the dose to achieve the optimal balance of efficacy and safety
■
■There is insufficient evidence from controlled trials to indicate how long treatment should
continue
Adverse effects
■
■Weight gain, somnolence and hyperglycaemia require monitoring
■
■Long-­term safety of risperidone in children and adolescents with ASD remains to be fully
determined
Using benzodiazepines to manage irritability and aggression in ASD is not recommended. However, it may be necessary to manage acute aggression with a benzodiazepine. The possibility of behavioural disinhibition that may worsen aggression must
be borne in mind.
The use of minocycline, arbaclofen or amantadine for irritability is not recommended
unless better evidence from double-­blind RCTs is available.6
Sleep disturbance
Children with ASD have significant sleep problems,81 with sleep-­onset insomnia,
­sleep-­maintenance insomnia and irregularities of the ­sleep–­wake cycle being the typical
problems encountered. It is essential to understand the aetiology of the sleep problem
before embarking on a course of treatment. Abnormalities in the melatonin system have
received some attention.82
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CHAPTER 5
Melatonin has been shown in 17 studies to be beneficial in children with ASD.83 A
meta-­analysis of five studies showed good efficacy with doses ranging from 1mg to
10mg and treatment lasting from 14 days to over 4 years.84 Melatonin is usually very
well tolerated.84,85 One RCT showed that, while melatonin improved sleep onset, the
child’s behaviour during the day did not improve.86 There is also evidence that melatonin combined with CBT is superior to melatonin only, CBT only and placebo in
reducing symptoms of insomnia.87
Risperidone may benefit sleep difficulties in those with extreme irritability. In the
anxious or depressed child, antidepressants may be beneficial. Insomnia due to hyper­
arousal may benefit from clonidine or clonazepam.88
Anxiety, OCD and depression
SSRIs have yet to show specific efficacy in ASD. Preliminary data from a ­randomised
placebo-­blind clinical trial showed beneficial effects of fluoxetine in reducing OCD
symptoms in children with ASD, although confounding factors precluded firm conclusions.89 In a systematic review,6 although risperidone was reported by ­several studies to
reduce OCD and anxiety symptoms in young people with ASD, the selection of participants with high levels of irritability did not allow firm conclusions to be drawn about
specific effects of risperidone on OCD and anxiety. There is little or no evidence for
treating anxiety or OCD symptoms with risperidone, clomipramine or an SSRI. There
are some data on buspirone effectively targeting anxiety in ASD90 and propranolol
showing positive cognitive effects in ASD.91 However, further evaluation is needed.
Guidance on doses of fluoxetine can be found in Box 5.3.
Use of fluoxetine in children and adolescents
When using fluoxetine to treat repetitive behaviours in ASD patients, doses much lower
than those used to treat depression are normally required. It is advisable to use a liquid
preparation and begin at the lowest possible dose, monitoring for adverse effects.
A suitable regimen is outlined in Box 5.3.
Box 5.3  Use of fluoxetine in children and adolescents
■
■Liquid fluoxetine (as hydrochloride): 20mg/5mL
■
■2.5mg/day a day for 1 week; note that 2.5mg = 0.625mL, which is difficult to measure accurately
■
■Follow with a flexible titration schedule based on weight, tolerability and adverse effects up to a
maximum dose of 0.8mg/kg/day (0.3mg/kg/day for week 2, 0.5mg/kg/day for week 3 and
0.8mg/kg/day subsequently)
■
■Reduction may be indicated if adverse effects are problematic
Adverse effects
■
■Monitor for treatment-­emergent suicidal behaviour, self-­harm and hostility, particularly at the
beginning of treatment
■
■Hyponatraemia is also ­possible –­ see Chapter 3

39 - References
References
Prescribing in children and adolescents
CHAPTER 5
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Aye SZ, et al. The effectiveness and adverse effects of D-­cycloserine compared with placebo on social and communication skills in individuals
with autism spectrum disorder. Cochrane Database Syst Rev 2021; 2:CD013457.
Brignell A, et al. Memantine for autism spectrum disorder. Cochrane Database Syst Rev 2022; 8:CD013845.
Dean OM, et al. A randomised, double blind, placebo-­controlled trial of a fixed dose of N-­acetyl cysteine in children with autistic disorder.
Aust N Z J Psychiatry 2017; 51:­241–­249.
Thom RP, et al. Recent updates in psychopharmacology for the core and associated symptoms of autism spectrum disorder. Curr Psychiatry
Rep 2021; 23:79.
Sathe N, et al. Nutritional and dietary interventions for autism spectrum disorder: a systematic review. Pediatrics 2017; 139:e20170346.
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37. Peretti S, et al. Diet: the keystone of autism spectrum disorder? Nutr Neurosci 2019; 22:­825–­839.
38. Yang Y, et al. Targeting gut microbiome: a novel and potential therapy for autism. Life Sci 2018; 194:­111–­119.
39. Lee YJ, et al. Advanced pharmacotherapy evidenced by pathogenesis of autism spectrum disorder. Clin Psychopharmacol Neurosci 2014;
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40. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Randomized, controlled, crossover trial of methylphenidate in
pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 2005; 62:­1266–­1274.
41. Posey DJ, et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of
secondary measures. Biol Psychiatry 2007; 61:­538–­544.
42. Santosh PJ, et al. Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity
­disorder: a retrospective and prospective effectiveness study. Child Care Health Dev 2006; 32:­575–­583.
43. Simonoff E, et al. Randomized controlled double-­blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability. J Child Psychol Psychiatry 2013; 54:­527–­535.
44. Sung M, et al. What’s in the pipeline? Drugs in development for autism spectrum disorder. Neuropsychiatr Dis Treat 2014; 10:­371–­381.
45. Siegel M, et al. Psychotropic medications in children with autism spectrum disorders: a systematic review and synthesis for evidence-­based
practice. J Autism Dev Disord 2012; 42:­1592–­1605.
46. Williamson ED, et al. Psychotropic medications in autism: practical considerations for parents. J Autism Dev Disord 2012; 42:­1249–­1255.
47. Rodrigues R, et al. Practitioner review: pharmacological treatment of attention-­deficit/hyperactivity disorder symptoms in children and youth
with autism spectrum disorder: a systematic review and meta-­analysis. J Child Psychol Psychiatry 2021; 62:­680–­700.
48. Coghill D, et al. European, randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-­deficit/
hyperactivity disorder. Eur Neuropsychopharmacol 2013; 23:­1208–­1218.
49. Arnold LE, et al. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-­controlled crossover pilot trial. J Am Acad Child
Adolesc Psychiatry 2006; 45:­1196–­1205.
50. Harfterkamp M, et al. A randomized double-­blind study of atomoxetine versus placebo for attention-­deficit/hyperactivity disorder symptoms
in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 2012; 51:­733–­741.
51. Handen BL, et al. Atomoxetine, parent training, and their combination in children with autism spectrum disorder and attention-­deficit/
hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2015; 54:­905–­915.
52. Smith T, et al. Atomoxetine and parent training for children with autism and attention-­deficit/hyperactivity disorder: a 24-­week extension
study. J Am Acad Child Adolesc Psychiatry 2016; 55:­868–­876.e862.
53. Scahill L, et  al. Extended-­release guanfacine for hyperactivity in children with autism spectrum disorder. Am J Psychiatry 2015;
172:­1197–­1206.
54. National Institute for Health and Care Excellence. Autism spectrum disorder in under 19s: support and management. Clinical Guidance 170
[CG170]. 2013 (last updated June 2021, last checked February 2024); https://www.nice.org.uk/guidance/CG170.
55. Kaplan G, et al. Psychopharmacology of autism spectrum disorders. Pediatr Clin North Am 2012; 59:­175–­187, xii.
56. McDougle CJ, et al. Atypical antipsychotics in children and adolescents with autistic and other pervasive developmental disorders. J Clin
Psychiatry 2008; 69 Suppl 4:­15–­20.
57. Parikh MS, et al. Psychopharmacology of aggression in children and adolescents with autism: a critical review of efficacy and tolerability.
J Child Adolesc Psychopharmacol 2008; 18:­157–­178.
58. DeVane CL, et al. Pharmacotherapy of autism spectrum disorder: results from the randomized BAART clinical trial. Pharmacotherapy 2019;
39:­626–­635.
59. Jesner OS, et al. Risperidone for autism spectrum disorder. Cochrane Database Syst Rev 2007; 2007:CD005040.
60. Scahill L, et al. Risperidone approved for the treatment of serious behavioral problems in children with autism. J Child Adolesc Psychiatr
Nurs 2007; 20:­188–­190.
61. Curran MP. Aripiprazole: in the treatment of irritability associated with autistic disorder in pediatric patients. PaediatrDrugs 2011;
13:­197–­204.
62. Fung LK, et al. Pharmacologic treatment of severe irritability and problem behaviors in autism: a systematic review and meta-­analysis.
Pediatrics 2016; 137 Suppl 2:­S124–­S135.
63. Douglas-­Hall P, et al. Aripiprazole: a review of its use in the treatment of irritability associated with autistic disorder patients aged 6-­17.
J Cent Nerv Syst Dis 2011; 3:­1–­11.
64. Iffland M, et  al. Pharmacological intervention for irritability, aggression, and self-­injury in autism spectrum disorder (ASD). Cochrane
Database Syst Rev 2023; 10:CD011769.
65. Caccia S. Safety and pharmacokinetics of atypical antipsychotics in children and adolescents. Paediatr Drugs 2013; 15:­217–­233.
66. Sharma A, et al. Efficacy of risperidone in managing maladaptive behaviors for children with autistic spectrum disorder: a meta-­analysis.
J Pediatr Health Care 2012; 26:­291–­299.
67. Kent JM, et al. Risperidone dosing in children and adolescents with autistic disorder: a double-­blind, placebo-­controlled study. J Autism Dev
Disord 2013; 43:­1773–­1783.
68. Maayan L, et al. Weight gain and metabolic risks associated with antipsychotic medications in children and adolescents. J Child Adolesc
Psychopharmacol 2011; 21:­517–­535.
69. Hermans RA, et al. The effect of therapeutic drug monitoring of risperidone and aripiprazole on weight gain in children and adolescents: the
SPACe 2: STAR (trial) protocol of an international multicentre randomised controlled trial. BMC Psychiatry 2022; 22:814.
70. Hirsch LE, et al. Aripiprazole for autism spectrum disorders (ASD). Cochrane Database Syst Rev 2016; 2016:CD009043.
71. Ghanizadeh A, et al. A head-­to-­head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized
double blind clinical trial. Child Psychiatry Hum Dev 2014; 45:­185–­192.
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72. Loebel A, et al. Lurasidone for the treatment of irritability associated with autistic disorder. J Autism Dev Disord 2016; 46:­1153–­1163.
73. Hollander E, et al. A double-­blind placebo-­controlled pilot study of olanzapine in childhood/adolescent pervasive developmental disorder.
J Child Adolesc Psychopharmacol 2006; 16:­541–­548.
74. Campbell M, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-­blind and placebo-­controlled study. J Am
Acad Child Adolesc Psychiatry 1995; 34:­445–­453.
75. Malone RP, et al. A double-­blind placebo-­controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry 2000; 57:­649–­654.
76. Donovan SJ, et al. Divalproex treatment for youth with explosive temper and mood lability: a double-­blind, placebo-­controlled crossover
design. Am J Psychiatry 2000; 157:­818–­820.
77. Stigler KA, et  al. Pharmacotherapy of irritability in pervasive developmental disorders. Child Adolesc Psychiatr Clin N Am 2008;
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40 - Tics and Tourettes syndrome in children and a
Tics and Tourette’s syndrome in children and adolescents

41 - Detection and treatment of comorbidity
Detection and treatment of comorbidity

42 - Education and behavioural treatments
Education and behavioural treatments

43 - Pharmacological treatments
Pharmacological treatments
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CHAPTER 5
Tics and Tourette’s syndrome in children and adolescents
Transient tics occur in ­5–­20% of children. Tourette’s syndrome (TS) occurs in about
0.7% of children and adolescents and is defined by persistent motor and vocal tics. As
many as 65% of individuals with TS will have no tics or only very mild tics by adult
life. Tics wax and wane over time and are variably exacerbated by external factors such
as stress, inactivity and fatigue, depending on the individual. Tics are about two to three
times more common in boys than girls.1 Functional tic disorders (involuntary physical
movements, often related to anxiety) have also been described in recent years.2 These
are typically seen in teenage girls.
Detection and treatment of comorbidity
Comorbid OCD, ADHD, ASD, depression, anxiety and behavioural problems are more
prevalent than would be expected by chance, and often cause the major impairment in
people with tic disorders.3 These comorbid conditions are usually treated first before
assessing the level of disability caused by the tics.
Education and behavioural treatments
Most people with tics do not require pharmacological treatment. Education is
­crucial for the individual with tics, their family and the people they interact
with, especially at school (Figure 5.2). Treatment aimed primarily at reducing tics
is warranted if the tics cause distress to the patient or are functionally disabling.
Behavioural interventions have been found to be effective with similar effect sizes to
antipsychotic medication.4,5 Habit reversal, comprehensive behavioural ­intervention
for tics and exposure and response prevention are the behavioural treatments of
choice.6
Pharmacological treatments
Studies of pharmacological interventions in TS are difficult to interpret for several
reasons:
■
■There is a large inter-­individual variation in tic frequency and severity. Small, randomised studies may include patients who are very different at baseline.
■
■The severity of tics in a given individual varies markedly over time, making it difficult
to separate drug effect from natural variation.
■
■The bulk of the literature consists of case reports, case series, open studies and underpowered, randomised studies. Publication bias is also likely to be an issue.
■
■A high proportion of patients have comorbid psychiatric illness. It can be difficult to
disentangle any direct effect on tics from an effect on the comorbid illness. This makes
it difficult to interpret studies that report improvements in global functioning rather
than specific reductions in tics.
■
■Large numbers of individuals attending clinics with TS appear to use complementary
or alternative therapies, with the majority reporting benefits and up to half finding

44 - Adrenergic 2 agonists
Adrenergic 2 agonists

45 - Antipsychotics
Antipsychotics
Prescribing in children and adolescents
CHAPTER 5
these more helpful compared with medication.7 Robust research about the use of
complementary or alternative therapies, their efficacy and potential adverse effects is
lacking8 and certainty of evidence for their use is very low.9
Adrenergic α2 agonists
Clonidine has been shown in open studies to reduce the severity and frequency of tics
but in one study this effect did not seem to be convincingly larger than placebo.10 Other
studies have shown more substantial reductions in tics.­11–­14 Therapeutic doses of clonidine are in the order of ­3–­5mcg/kg, and the dose should be built up gradually. A transdermal patch has also shown effectiveness.15 The main adverse effects are sedation,
postural hypotension and depression. Patients and their families should be informed not
to stop clonidine suddenly because of the risk of rebound hypertension. Guanfacine also
has some evidence of effectiveness in the treatment of tics.16,17 The efficacy of clonidine
(but not of guanfacine) was demonstrated in a 2023 systematic review and network
meta-­analysis of double-­blind RCTs in TS which included children, adolescents and
adults.9 Adrenergic α2 agonists may also be used in children with ADHD whose tics
deteriorate with stimulant medication.18
Antipsychotics
Adverse effects of antipsychotics may outweigh their beneficial effects in the treatment
of tics so it is recommended that clonidine or guanfacine is generally tried first
(Figure 5.2). Antipsychotics may, however, be more effective than adrenergic α2 ­agonists
in alleviating tics.9
A number of first-­generation antipsychotics have been used in TS. In a Cochrane
review, pimozide demonstrated robust efficacy in a meta-­analysis of six trials.19 In these
trials, pimozide was compared with haloperidol (one trial), placebo (one trial), haloperidol and placebo (two trials) and risperidone (two trials) and was found to be more effective than placebo, as effective as risperidone and slightly less effective than haloperidol
in reducing tics. It was associated with less severe adverse effects than haloperidol but
did not differ from risperidone in that respect. ECG monitoring is essential for pimozide
and haloperidol. Haloperidol is often poorly tolerated. Tiapride may also be effective,
but evidence may not be generalisable and it has limited availability.9
SGAs, in particular aripiprazole, have in recent years been used more commonly for
the treatment of TS.20 Aripiprazole is an effective and well-­tolerated treatment of children with TS (and also tics21). A 10-­week multicentre double-­blind randomised placebo-­
controlled trial (N = 61) demonstrated the efficacy of aripiprazole in tic ­reduction in
TS. Treatment was associated with significantly decreased serum prolactin concentration, increased mean body weight (by 1.6kg), body mass index and waist circumference.22 Aripiprazole was also found to be effective in another randomised double-­blind
placebo-­controlled trial (N = 133) comparing low-­dose aripiprazole (5mg/day if <50kg;
10mg/day if ≥50kg), high-­dose aripiprazole (10mg/day if <50kg; 20mg/day if ≥50kg)
or placebo for 8 weeks.23 At week 8, tics were reduced in both the high-­dose group and
the low-­dose group, with 69% of patients in the low-­dose group and 74% in the high-­
dose group being very much improved or much improved, compared with 38% in the

46 - Other drugs
Other drugs
616
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CHAPTER 5
placebo group. Surprisingly, a higher proportion of children in the low-dose group
(18.2%) compared with the high-­dose group (9.3%) and placebo group (9.1%) gained
clinically significant weight (≥7%) which may have been related to a lower average
baseline weight in this group.
Several case series also support the use of aripiprazole.­24–­27 A study evaluating the
metabolic side effects of aripiprazole (N = 25) and pimozide (N = 25) in TS over a
­24-­month period demonstrated that treatment was not associated with significant
increase in body mass index. However, pimozide treatment was associated with increases
in blood glucose that did not plateau from 12 to 24 months, aripiprazole treatment was
associated with increased cholesterol and both medications were associated with
increased triglycerides.28 Two meta-­analyses support the efficacy of aripiprazole.29,30 One
study31 suggests twice-weekly administration may be better tolerated than daily dosing.
A small RCT (N = 24) comparing aripiprazole with sodium ­valproate in children with TS
demonstrated a statistically significant difference in tic reduction favouring
aripiprazole.32
Risperidone has, in addition to the studies mentioned, also been shown to be more
effective than placebo in a small (N = 34) randomised study.33 Fatigue and increased
appetite were problematic in the risperidone arm and a mean weight gain of 2.8kg over
8 weeks was reported. One small RCT found risperidone and clonidine to be equally
effective.34 A small double-­blind crossover study suggested that olanzapine35 may be
more effective than pimozide. Sulpiride has been shown to be effective and relatively
well tolerated,36 as has ziprasidone.37 Open studies support the efficacy of quetiapine38
and olanzapine.39,40 One very small crossover study (N = 7) found no effect for clozapine.41 Antipsychotic medications may not differ from each other in terms of efficacy for
tics, with low to very low certainty of evidence for this comparison.9
Overall, metabolic side effects and weight gain are common with second-generation
antipsychotics, even aripiprazole, so benefit/risk ratios need careful discussion.42
Other drugs
A small, double-­blind placebo-­controlled crossover trial of baclofen was suggestive of
beneficial effects in overall impairment rather than a specific effect on tics.43 The
numerical benefits shown in this study did not reach statistical significance. Similarly, a
double-­blind placebo-­controlled trial of nicotine augmentation of haloperidol found
beneficial effects in overall impairment rather than a specific effect on tics.44 These benefits persisted for several weeks after nicotine (in the form of patches) was withdrawn.
Nicotine patches were associated with a high prevalence of nausea and vomiting (71%
and 40%, respectively). The authors suggest that use as required may be appropriate.
Flutamide, an antiandrogen, has been the subject of a small RCT in adults with TS.
Modest, short-­lived effects were seen in motor but not phonic tics.45 A small RCT
showed significant advantages for metoclopramide over placebo46 and for topiramate
over placebo. A meta-­analysis identified 14 RCTs (all from China) comparing topiramate with haloperidol or tiapride. It concluded that owing to the overall low quality of
the study designs, there is not enough evidence to support the routine use of topiramate
in clinical practice.47 Tetrabenazine may be useful as an add-­on treatment.48 Ecopipam,
a D1 receptor antagonist, was also found to be effective in the treatment of tics in a
Prescribing in children and adolescents
CHAPTER 5
randomised placebo-­controlled crossover study including children and adolescents
with TS.49 A second trial (n = 153)50 confirmed the efficacy of ecopipam. The monoamine depleting agents deutetrabenazine and valbenazine, the selective serotonin 5-­HT3
receptor antagonist ondansetron and pergolide, a D1-­D2-­D3 agonist, are probably not
effective.9,51
Case reports or case series describing positive effects have been published for
­clomiphene,52 tramadol,53 ketanserin,54 cyproterone,55 levetiracetam,56 pregabalin57 and
cannabis.58 A Cochrane review of cannabinoids concluded that there was little if any current evidence for efficacy59 and, despite a strong biological rationale for use, their overall
efficacy and safety remain largely unknown.60 Many other drugs have been reported to
be effective in single case reports. Patients in these reports all had comorbid psychiatric
illness, making it difficult to determine the effect of these drugs on TS alone.
Botulinum toxin has been used to treat bothersome or painful focal motor tics,
­particularly those affecting neck muscles.42 However, a 2018 Cochrane review expressed
uncertainty about its place in the treatment of tics owing to the low quality of available
evidence.61
There may be a subgroup of children who develop tics and/or OCD in association
with streptococcal or other infections or triggers. This group has been given (in the case
of Streptococcus) the acronym PANDAS (paediatric autoimmune neuropsychiatric
­disorder associated with Streptococcus)62 or, more broadly, PANS (paediatric acute-­
onset neuropsychiatric syndrome).63 This is thought to be an autoimmune-­mediated
effect, and there have been trials of immune-­modulatory therapy in these children as
well as treatment with antibiotics for active infections and also as preventative
­treatment. More research in this area is warranted.
It is extremely rare in practice to get to this point – almost all cases
can be effectively treated by recommendations above this point.
Not fully effective
Poorly tolerated
Not effective
Educational and behavioural
treatment
Clonidine or guanfacine
Antipsychotic treatment,
e.g. aripiprazole or risperidone
Consider older or more
experimental treatments
(see text)
Not fully effective
Figure 5.2  Summary of recommendations for the treatment of tics and Tourette’s syndrome.

47 - References
References
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CHAPTER 5
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Scahill L, et al. A placebo-­controlled trial of risperidone in Tourette syndrome. Neurology 2003; 60:­1130–­1135.
Prescribing in children and adolescents
CHAPTER 5
34. Gaffney GR, et al. Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child
Adolesc Psychiatry 2002; 41:­330–­336.
35. Onofrj M, et al. Olanzapine in severe Gilles de la Tourette syndrome: a 52-­week double-­blind cross-­over study vs. low-­dose pimozide. J
Neurol 2000; 247:­443–­446.
36. Robertson MM, et al. Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol 1990; 13:­229–­235.
37. Sallee FR, et  al. Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc
Psychiatry 2000; 39:­292–­299.
38. Mukaddes NM, et al. Quetiapine treatment of children and adolescents with Tourette’s disorder. J Child Adolesc Psychopharmacol 2003;
13:­295–­299.
39. Budman CL, et al. An open-­label study of the treatment efficacy of olanzapine for Tourette’s disorder. J Clin Psychiatry 2001; 62:­290–­294.
40. McCracken JT, et al. Effectiveness and tolerability of open label olanzapine in children and adolescents with Tourette syndrome. J Child
Adolesc Psychopharmacol 2008; 18:­501–­508.
41. Caine ED, et al. The trial use of clozapine for abnormal involuntary movement disorders. Am J Psychiatry 1979; 136:­317–­320.
42. Roessner V, et al. Pharmacological treatment of tic disorders and Tourette syndrome. Neuropharmacology 2013; 68:­143–­149.
43. Singer HS, et  al. Baclofen treatment in Tourette syndrome: a double-­blind, placebo-­controlled, crossover trial. Neurology 2001;
56:­599–­604.
44. Silver AA, et al. Transdermal nicotine and haloperidol in Tourette’s disorder: a double-­blind placebo-­controlled study. J Clin Psychiatry 2001;
62:­707–­714.
45. Peterson BS, et al. A double-­blind, placebo-­controlled, crossover trial of an antiandrogen in the treatment of Tourette’s syndrome. J Clin
Psychopharmacol 1998; 18:­324–­331.
46. Nicolson R, et al. A randomized, double-­blind, placebo-­controlled trial of metoclopramide for the treatment of Tourette’s disorder. J Am Acad
Child Adolesc Psychiatry 2005; 44:­640–­646.
47. Yang CS, et al. Topiramate for Tourette’s syndrome in children: a meta-­analysis. Pediatr Neurol 2013; 49:­344–­350.
48. Porta M, et al. Tourette’s syndrome and role of tetrabenazine: review and personal experience. Clin Drug Invest 2008; 28:­443–­459.
49. Gilbert DL, et al. Ecopipam, a D1 receptor antagonist, for treatment of Tourette syndrome in children: a randomized, placebo-­controlled
crossover study. Mov Disord 2018; 33:­1272–­1280.
50. Gilbert DL, et al. Ecopipam for Tourette syndrome: a randomized trial. Pediatrics 2023; 151:e2022059574.
51. Chou CY, et al. Emerging therapies and recent advances for Tourette syndrome. Heliyon 2023; 9:e12874.
52. Sandyk R. Clomiphene citrate in Tourette’s syndrome. Int J Neurosci 1988; 43:­103–­106.
53. Shapira NA, et al. Novel use of tramadol hydrochloride in the treatment of Tourette’s syndrome. J Clin Psychiatry 1997; 58:­174–­175.
54. Bonnier C, et al. Ketanserin treatment of Tourette’s syndrome in children. Am J Psychiatry 1999; 156:­1122–­1123.
55. Izmir M, et al. Cyproterone acetate treatment of Tourette’s syndrome. Can J Psychiatry 1999; 44:­710–­711.
56. Awaad Y, et al. Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome. Mov Disord 2005; 20:­714–­718.
57. Hienert M, et al. Pregabalin in Tourette’s syndrome: a case series. Am J Psychiatry 2016; 173:­1242–­1243.
58. Sandyk R, et al. Marijuana and Tourette’s syndrome. J Clin Psychopharmacol 1988; 8:­444–­445.
59. Curtis A, et al. Cannabinoids for Tourette’s syndrome. Cochrane Database Syst Rev 2009; 2009:CD006565.
60. Artukoglu BB, et al. The potential of cannabinoid-­based treatments in Tourette syndrome. CNS Drugs 2019; 33:­417–­430.
61. Pandey S, et al. Botulinum toxin for motor and phonic tics in Tourette’s syndrome. Cochrane Database Syst Rev 2018; 1:CD012285.
62. Martino D, et  al. The PANDAS subgroup of tic disorders and childhood-­onset obsessive-­compulsive disorder. J Psychosom Res 2009;
67:­547–­557.
63. Chang K, et al. Clinical evaluation of youth with pediatric acute-­onset neuropsychiatric syndrome (PANS): recommendations from the 2013
PANS Consensus Conference. J Child Adolesc Psychopharmacol 2015; 25:­3–­13.

48 - Melatonin in the treatment of insomnia in chi
Melatonin in the treatment of insomnia in children and adolescents

49 - Efficacy
Efficacy
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The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
Melatonin in the treatment of insomnia in children and adolescents
Insomnia is a common symptom in childhood. Underlying causes may be behavioural
(inappropriate sleep associations or bedtime resistance), physiological (delayed sleep
phase syndrome) or related to underlying mood disorders (anxiety, depression and
bipolar disorder). All forms of insomnia are more common in children with learning
difficulties, autism, ADHD and sensory impairments (particularly visual). Although
behavioural interventions should be the primary intervention and have a robust
­evidence base, exogenous melatonin is now the first-­line medication prescribed for
childhood insomnia (Figure 5.3).1
Melatonin is a hormone that is produced by the pineal gland in a circadian manner.
The evening rise in melatonin, enabled by darkness, precedes the onset of natural sleep
by about 2 hours.2 Melatonin is involved in the induction of sleep and in synchronisation of the circadian system.
There is a wide variety of unlicensed fast-­release, slow-­release and liquid preparations
of melatonin. Many products rely on food grade rather than pharmaceutical grade melatonin and some are expensive. In 2018 the European Medicines Agency and UK MHRA
approved Slenyto, a paediatric-­appropriate prolonged-­release melatonin minitablet, for
children with autism and insomnia. This approval was on the basis of a phase III multicentre randomised placebo-­controlled study of children with autism. Results of the study
included clinically significant improvement in caregivers’ diary-­reported sleep latency,
total sleep time and longest sleep period.3 Effects were maintained in the long ­term. The
medication was well tolerated and no unexpected safety issues were reported. The study
was the only ‘class 1’ rated study in the 2020 America Academy of Neurology practice
guideline on the treatment for insomnia and disrupted sleep behaviour in ­children and
adolescents with ASD.4 Secondary outcomes showed improvements in children’s social
functioning and behaviour, and caregivers’ well-­being. A meta-­analysis of melatonin in
ASD came to similar, positive conclusions.5
Two RCTs6,7 showed melatonin had comparable benefits when used to treat children with ADHD and insomnia. On this basis, the MHRA in the UK has approved
various immediate-­release (tablet, e.g. Adaflex) and liquid (e.g. Colonis, Ceyesto)
melatonin preparations for the management of sleep-­onset insomnia in children with
ADHD.
There is less evidence (and clinical consensus) for the use of melatonin in ­typically
developing children, although a 2023 meta-­analysis provided a conditional recommendation ‘for use of melatonin in children and adolescents ­2–­20 years, who despite optimisation of sleep hygiene practices, continue to present with difficulties in daily
functioning, due to chronic insomnia attributed to an underlying disorder’.8
Efficacy
A meta-­analysis that included adult and paediatric studies of melatonin in primary
sleep disorders demonstrated that melatonin modestly decreases sleep-­onset latency,
increases total sleep time and improves overall sleep quality; effects that appear not to
dissipate with continued melatonin use.9 A more recent (2022) analysis confirmed
­benefits only for sleep latency and sleep duration.10

50 - Adverse effects
Adverse effects

51 - Dose
Dose
Prescribing in children and adolescents
CHAPTER 5
Adverse effects
Many of the children who have received melatonin in RCTs and published case series
had developmental problems and/or sensory deficits. The scope for detecting subtle
adverse effects in this population is limited. Screening for adverse effects was not r­outine
in all studies. In early published accounts, melatonin was reported to worsen seizures11
and exacerbate asthma.12,13 Other reported adverse effects included headache, depression, restlessness, confusion, nausea, tachycardia and pruritis.14,15 However, in more
recent and larger placebo-­controlled studies involving children with learning difficulty,
autism and epilepsy,3,­16–­18 there were no excess adverse effects in the treatment group
over placebo and, in particular, seizures were not worsened. A Cochrane review also
found no worsening of seizure frequency in patients with epilepsy who were given
melatonin.19 Melatonin has no detectable impact on puberty.20
Dose
The cut-­off point between physiological and pharmacological doses in children is less
than 500mcg. Physiological doses (i.e. <500mcg) of melatonin may result in very high
receptor occupancy. The doses used in RCTs and published case series vary hugely with
between 500mcg and 5mg doses usually being used, although much lower and higher
doses have been studied. In one large RCT, 18% of children seemed to respond to a
500mcg dose but others seemed to require much higher doses (12mg).18 Increasing
doses above 5mg is likely to provoke the direct sedative effects of melatonin rather than
its sleep phase-­shifting properties. This might be necessary and helpful for some children with severe and bilateral brain injury.
No response
to 6–10mg
Response
Sleep hygiene
Parent-led sleep behavioural
interventions
Melatonin:
Use licensed product 2–5mg
Consider use of 6–10mg
if response poor
Discontinue melatonin
Identify and treat
secondary causes
Not effective
Childhood insomnia in
association with ASD or
ADHD
Continue at minimum
effective dose
Figure 5.3  Summary of recommendations in the treatment of insomnia.

52 - References
References
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The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
References
Gringras P. When to use drugs to help sleep. Arch Dis Child 2008; 93:­976–­981.
Macchi MM, et al. Human pineal physiology and functional significance of melatonin. Front Neuroendocrinol 2004; 25:­177–­195.
Gringras P, et al. Efficacy and safety of pediatric prolonged-­release melatonin for insomnia in children with autism spectrum disorder. J Am
Acad Child Adolesc Psychiatry 2017; 56:­948–­957.e944.
Williams Buckley A, et al. Practice guideline: treatment for insomnia and disrupted sleep behavior in children and adolescents with autism
spectrum disorder: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of
Neurology. Neurology 2020; 94:­392–­404.
Xiong M, et al. Efficacy of melatonin for insomnia in children with autism spectrum disorder: a meta-­analysis. Neuropediatrics 2023;
54:­167–­173.
Van der Heijden KB, et al. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-­onset insomnia. J Am Acad Child
Adolesc Psychiatry 2007; 46:­233–­241.
Weiss MD, et al. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child
Adolesc Psychiatry 2006; 45:­512–­519.
Edemann-­Callesen H, et al. Use of melatonin for children and adolescents with chronic insomnia attributable to disorders beyond indication:
a systematic review, meta-­analysis and clinical recommendation. EClinicalMedicine 2023; 61:102049.
Ferracioli-­Oda E, et al. Meta-­analysis: melatonin for the treatment of primary sleep disorders. PLoS One 2013; 8:e63773.
Salanitro M, et al. Efficacy on sleep parameters and tolerability of melatonin in individuals with sleep or mental disorders: a systematic review
and meta-­analysis. Neurosci Biobehav Rev 2022; 139:104723.
Sheldon SH. Pro-­convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998; 351:1254.
Maestroni GJ. The immunoneuroendocrine role of melatonin. J Pineal Res 1993; 14:­1–­10.
Sutherland ER, et  al. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol 2003;
112:­513–­517.
Chase JE, et al. Melatonin: therapeutic use in sleep disorders. Ann Pharmacother 1997; 31:­1218–­1226.
Jan JE, et al. Melatonin treatment of sleep-­wake cycle disorders in children and adolescents. Dev Med Child Neurol 1999; 41:­491–­500.
Coppola G, et al. Melatonin in wake-­sleep disorders in children, adolescents and young adults with mental retardation with or without
­epilepsy: a double-­blind, cross-­over, placebo-­controlled trial. Brain Dev 2004; 26:­373–­376.
Garstang J, et al. Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care
Health Dev 2006; 32:­585–­589.
Gringras P, et al. Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo ­controlled
trial. BMJ 2012; 345:e6664.
Brigo F, et al. Melatonin as add-­on treatment for epilepsy. Cochrane Database Syst Rev 2016; 2016:CD006967.
Malow BA, et al. Sleep, growth, and puberty after 2 years of prolonged-­release melatonin in children with autism spectrum disorder. J Am
Acad Child Adolesc Psychiatry 2012; 60:­252–­261.e3.

53 - Rapid tranquillisation (RT) in children and a
Rapid tranquillisation (RT) in children and adolescents
Prescribing in children and adolescents
CHAPTER 5
Rapid tranquillisation (RT) in children and adolescents
As in adults, a comprehensive assessment and effective treatment plan undertaken by
staff skilled in the use of de-­escalation techniques and appropriate placement of the
patient are key to minimising the need for enforced parenteral medication. The
­differential diagnoses for agitated or challenging behaviour can be broad, but there is
concern that RT may be disproportionately used in a neurodiverse population where
other strategies may be more appropriate and the outcome more predictable.1,2
Healthcare professionals undertaking RT and/or restraint in children and adolescents should be trained and competent in undertaking these procedures in this population and should be clear about the legal context for any restrictive practices they employ.
Be particularly cautious when considering high-­potency antipsychotic medication (e.g.
haloperidol) especially for those who are neuroleptic naïve, because of the increased
risk of acute dystonic reactions in this age group.3 Children are particularly prone to
acute extrapyramidal effects of psychotropic and physical medication.4 In the UK,
NICE recommends using intramuscular lorazepam (and recommends no other drug).5
Evidence suggests that lorazepam is effective (at a median dose of 1mg) and rarely
causes respiratory depression resulting in oxygen desaturation.1 Reviews support the
use of a range of SGA drugs6 with the most frequently used agent being olanzapine,
which has evidence of its safety and efficacy.7
A wide dose range is given here for medication used in RT. This is partly a consequence of the wide range of body mass in individuals aged from under 10 to 18 years.
Caution is required, especially for younger children, but in older adolescents consider
the use of adult doses, especially in those who are not drug naïve and where doses at
the lower end of the quoted dose range have proved ineffective.
A summary is given in Table 5.11.
Table 5.11  Recommended drugs for rapid tranquillisation if the oral route is refused or has proven ineffective.
Medication
Dose
Onset of action
Comment
Olanzapine IM8,9
2.­5–­10mg
­15–­30 minutes
Possibly increased risk of respiratory
depression when administered with
benzodiazepines, particularly if alcohol has
been consumed. Separate administration by
at least 1 hour.
Haloperidol IM10
0.­025–­0.075mg/kg/dose
(max. 2.5mg) IM
 
Adolescents >12 years
can receive the adult
dose (2.­5–­5mg)
­20–­30 minutes
Must have parenteral anticholinergics
present in case of laryngeal spasm or other
dystonia (young people more vulnerable to
severe dystonia).
 
Adult data suggest co-­administration of
promethazine may reduce EPS risk.11
 
ECG is essential
Lorazepam* IM12
<12 years: 0.­5–­1mg;
12 years: 0.5-­2mg
­20–­40 minutes
Slower onset of action than midazolam
 
Only treatment recommended by NICE
 
Flumazenil is the reversing agent for all
benzodiazepines.
(Continued )
624
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 5
Oral medication should always be offered (and repeated if necessary if the young
person is willing to take it) before resorting to parenteral treatment. Oral alternatives
such as buccal midazolam14 and inhaled loxapine20 have not been widely investigated in
children in RT and have limited availability. Buccal midazolam is commonly used for
seizures in children.
Monitoring after RT is the same as in adults (see Chapter 3).
Medication
Dose
Onset of action
Comment
Midazolam* IM,
IV or buccal12
0.­1–­0.15mg/kg IM
 
Buccal midazolam
­300–­500mcg/kg or ­
6–­10 years = 7.5mg;
10 years = 10mg
­10–­20 min IM
(­1–­3 min IV)
Quicker onset and shorter duration of
action than lorazepam or diazepam
 
IV administration should only be used (usually
as a last resort) with extreme caution and
where resuscitation facilities are available.
 
Quicker onset and shorter duration of
action than haloperidol
 
When given as buccal liquid, onset of action
is ­15–­30 minutes.13 There are some
published data of its use in mental health
but only in adults;14 buccal liquid is
unlicensed for this use.
Diazepam* IV
(not for IM
administration)15
0.1mg/kg/dose by slow
IV injection
 
Max. 40mg total daily
dose <12 years and
60mg >12 years
­1–­3 minutes
Long half-­life that does not correlate with
length of sedation
 
Possibility of accumulation
 
Never give as IM injection.
Ziprasidone IM16,17
­10–­20mg
­15–­30 minutes IM
Apparently effective
 
QT prolongation is of concern in this patient
group.
 
ECG is essential.
Aripiprazole IM18,19
9.75mg
­15–­30 minutes
Evidence of effectiveness in adults but no
clinical trial data for children and adolescents
Promethazine IM
<12 years: ­5–­25mg
(max. 50mg/day)
 
12 years: ­25–­50mg
(max. 100mg/day)
Up to 60 minutes
An effective sedative, although has a slow
onset of action. Useful if the cause of
behavioural disturbance is unknown and
there is concern about the use of
antipsychotic medication in a child or young
person.
*Note that young people are particularly vulnerable to disinhibitory reactions with benzodiazepines. EPS, extrapyramidal symptoms.
Table 5.11  (Continued)

54 - References
References
Prescribing in children and adolescents
CHAPTER 5
References
Kendrick JG, et al. Pharmacologic management of agitation and aggression in a pediatric emergency department – a retrospective cohort
study. J Pediatric Pharmacol Therapeutics 2018; 23:­455–­459.
Wolpert KH, et al. Behavioral management of children with autism in the emergency department. Pediatr Emerg Care 2023; 39:­45–­50.
National Institute for Health and Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management.
Clinical Guidance [CG155]. 2013 (last updated October 2016, last checked October 2023); https://www.nice.org.uk/guidance/cg155.
Chang MY, et al. Drug-­induced extrapyramidal symptoms at the pediatric emergency department. Pediatr Emerg Care 2020; 36:­468–­472.
National Institute for Health and Care Excellence. Violence and aggression: short-­term management in mental health, health and community
settings. NICE Guideline [NG10]. 2015 (last checked October 2023); https://www.nice.org.uk/guidance/ng10.
Rudolf F, et al. A retrospective review of antipsychotic medications administered to psychiatric patients in a tertiary care pediatric emergency
department. J Pediatric Pharmacol Therapeutics 2019; 24:­234–­237.
Cole JB, et al. The use, safety, and efficacy of olanzapine in a level I pediatric trauma center emergency department over a 10-­year period.
Pediatr Emerg Care 2020; 36:­70–­76.
Breier A, et al. A double-­blind, placebo-­controlled dose-­response comparison of intramuscular olanzapine and haloperidol in the treatment
of acute agitation in schizophrenia. Arch Gen Psychiatry 2002; 59:­441–­448.
Lindborg SR, et al. Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients. Psychiatry
Res 2003; 119:­113–­123.
Powney MJ, et al. Haloperidol for psychosis-­induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev 2012;
11:CD009377.
TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam
versus haloperidol plus promethazine. BMJ 2003; 327:­708–­713.
Nobay F, et al. A prospective, double-­blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of
violent and severely agitated patients. Acad Emerg Med 2004; 11:­744–­749.
Schwagmeier R, et  al. Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharmacol 1998;
46:­203–­206.
Taylor D, et al. Buccal midazolam for agitation on psychiatric intensive care wards. Int J Psychiatry Clin Pract 2008; 12:­309–­311.
Nunn K, et al. Medication table. In: Nunn KP, Dey C, eds. The Clinician’s Guide to Psychotropic Prescribing in Children and Adolescents,
1st edn. Sydney: Glad Publishing 2003:­383–­452.
Khan SS, et al. A naturalistic evaluation of intramuscular ziprasidone versus intramuscular olanzapine for the management of acute agitation
and aggression in children and adolescents. J Child Adolesc Psychopharmacol 2006; 16:­671–­677.
Staller JA. Intramuscular ziprasidone in youth: a retrospective chart review. J Child Adolesc Psychopharmacol 2004; 14:­590–­592.
Sanford M, et al. Intramuscular aripiprazole: a review of its use in the management of agitation in schizophrenia and bipolar I disorder.
CNS Drugs 2008; 22:­335–­352.
National Institute for Health and Clinical Excellence. Aripiprazole for schizophrenia in people aged 15 to 17 years. Technology Appraisal
[TA213]. 2011 (last checked October 2023); https://www.nice.org.uk/guidance/ta213.
Lesem MD, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-­controlled study of
inhaled loxapine. Br J Psychiatry 2011; 198:­51–­58.

55 - Doses of commonly used psychotropic drugs in
Doses of commonly used psychotropic drugs in children and adolescents

56 - References
References
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CHAPTER 5
Doses of commonly used psychotropic drugs in children
and adolescents
Commonly used psychotropic drugs are presented in Table 5.12.
References
Paediatric Formulary Committee. BNF for Children (online). London: BMJ, Pharmaceutical Press, and RCPCH Publications; http://www.
medicinescomplete.com.
Merative US LP. Micromedex. 2024; https://www.micromedexsolutions.com/home/dispatch/.
Gov.UK. Guidance: Valproate use by women and girls. 2018 (last updated January 2024); https://www.gov.uk/guidance/valproate-­use-­by-
­women-­and-­girls.
Table 5.12  Starting doses of commonly used psychotropic drugs in children and adolescents.1,2
Drug
Starting dose*
Comment
Antipsychotics
Aripiprazole
2mg
Adjust dose according to response and adverse effects.
Clozapine
6.­25–­12.5mg
Use plasma levels to determine maintenance dose.
Lurasidone
18.5mg (20mg)
to 37mg (40mg)
Adjust dose according to response and adverse effects.
Olanzapine
2.­5–­5mg
Adjust dose according to response and adverse effects.
Quetiapine
25mg
Effective dose usually in the range ­150–­200mg daily.
Risperidone
0.­25–­2mg
Adjust dose according to response and adverse effects.
Antidepressants
Citalopram
10mg daily
Effective dose ­10–­40mg (note QT effects)
Escitalopram
5mg/day
Effective dose ­10–­20mg (note QT effects)
Fluoxetine
­5–­10mg/day
Adjust dose according to response and adverse effects.
Sertraline
25mg daily
Effective dose usually in the range ­50–­100mg daily.
Other drugs
Lithium
­100–­200mg/day
lithium carbonate
Use plasma levels to determine maintenance dose.
Melatonin
­1–­2mg at night
Effective dose ­2–­10mg
Valproate
­10–­20mg/kg/day
in divided doses
Use plasma levels to determine maintenance dose. Do not
offer valproate to girls or young women of child-­bearing
potential unless there is a pregnancy prevention
programme (PPP) in place.1,3
*Suggested approximate oral starting doses (see primary literature for doses in individual indications). Lower dose in
suggested range is for children weighing less than 25kg.