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National Collaborating Centre for Mental Health (UK). Depression in Children and Young People: Identification and Management in Primary, Community and Secondary Care. Leicester (UK): British Psychological Society; 2005. (NICE Clinical Guidelines, No. 28.)

7Pharmacological and physical treatment of depression in children and young people

7.1. Introduction

In the absence, until relatively recently, of good quality controlled trials of pharmacological treatments in children and young people, treatment practice has relied on extrapolation from the results of studies on adults. The mainstay of pharmacological treatment has been antidepressant drugs, initially tricyclic antidepressants and more recently selective serotonin reuptake inhibitors (SSRIs) and other atypical antidepressants. The herbal preparation, St John's wort, has been used for centuries for medicinal purposes including the treatment of depression, but little is known about its use in children and young people. Other drugs such as lithium salts and antipsychotics have been tried but their use is rare and usually reserved for young people with severe, psychotic and chronic depression. Lithium has also been used to prevent relapse of depression.

7.2. Prescribing for children and young people

In the UK, drug manufacturers do not recommend these drugs for the treatment of depression in those under the age of 18 years and the drugs themselves are not licensed for this use in this age group. However despite this, considerable clinical experience of their use in young people has been developed, initially from open trials and more recently from controlled evaluations of drug treatments.

In 2000, the Royal College of Paediatrics and Child Health issued a policy statement on the use of unlicensed medicines or the use of licensed medicines for unlicensed applications, in children and young people. This states clearly that such use is necessary in paediatric practice and that doctors are legally allowed to prescribe unlicensed medicines where there are no suitable alternatives and where the use is justified by a responsible body of professional opinion (Joint Royal College of Paediatrics and Child Health/Neonatal and Paediatric Pharmacists Group Standing Committee on Medicines, 2000).

7.3. The Regulatory Framework

In December 2003, following a review by an Expert Working Group of the Committee on Safety of Medicines (CSM, 2003), the CSM advised that citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine should not be used as new therapy for the treatment of depression in under 18 year olds (Duff, 2003c). Despite the lack of a marketing authorisation for fluoxetine in the treatment of major depressive disorder at that time, the CSM advised that the balance of risks and benefits for this drug was favourable.

Although the CSM used the word ‘contraindicated’ in relation to drugs other than fluoxetine in the treatment of depression in under 18s, its advice was also clear that child and adolescent psychiatrists are able to prescribe SSRIs other than fluoxetine in certain circumstances, for example, where drug treatment is indicated but a patient is intolerant of fluoxetine.

In April 2005 the Committee on Human Medicinal Products (CHMP) of the European Medicines Evaluation Agency13 (EMEA) also issued advice on the paediatric use of SSRIs and SNRIs. This advice referred to all paediatric use of these drugs, not just the treatment of depression. The CHMP noted that suicide-related behaviour (suicide attempt/self-harm and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with these antidepressants compared with those treated with placebo and advised that these products should not be used in children and adolescents except in their approved indications – usually not depression. However, like the CSM, the CHMP also made it clear that doctors may make decisions based on the individual clinical needs of a child or an adolescent to use these products for the treatment of depression or anxiety. In such circumstances the CHMP recommended that patients be monitored carefully for the appearance of suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment.

The Food and Drug Administration14 (FDA) issued a Public Health Advisory announcing a multi-pronged strategy to warn the public about the increased risk of suicidal thoughts and behaviour (‘suicidality’) in children and adolescents being treated with antidepressant medications in October 2004. The FDA directed manufacturers to add a ‘black box’ warning to the healthcare professional labelling of all antidepressant medications to describe this risk and emphasize the need for close monitoring of patients started on these medications. The FDA also determined that a Patient Medication Guide (MedGuide), should be developed and given to patients receiving the drugs to advise them of the risk and precautions that could be taken.

Fluoxetine is currently the only medication approved by the FDA in the US to treat depression in children and adolescents but these labelling changes are to be applied to the entire category of antidepressant. The new warning language does not prohibit the use of antidepressants in children and adolescents; rather, it warns of the risk of suicidality and encourages prescribers to balance this risk with clinical need.

A template for the labelling and medication guide issued by the FDA in January 2005 suggests that prescribers, families and caregivers of paediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behaviour, and other symptoms, as well as the emergence of suicidality. It is suggested that monitoring is especially important in the early stages of treatment and at times of change in dosage.

7.4. Antidepressant drugs

7.4.1. Introduction

Tricyclic antidepressants are thought to influence mood via their ability to block the synaptic re-uptake of monoamines including noradrenaline (NA), 5-hydroxytryptamine (5HT or serotonin) and dopamine (DA). However, these drugs also have significant side effects and high toxicity in overdose. As a result, newer types of antidepressants have been developed that retain the ability to elevate mood whilst having fewer side effects and being less toxic in overdose. These drugs are also thought to influence mood via their ability to raise levels of intra-synaptic monoamines.

7.4.2. Databases searched and inclusion criteria

Table 14Databases searched and inclusion criteria for clinical effectiveness and safety of antidepressant drugs

Electronic databasesMEDLINE, EMBASE, PsycINFO, Cochrane Library
Search datesDatabases: inception to January 2004 (key journals searched using the electronic table of contents service until September 2004)
Study designRCT
Patient populationParticipants aged 5–18 years diagnosed with depression
Interventions

Tricyclic and related antidepressants

SSRIs: fluoxetine, paroxetine, sertraline, citalopram

Other atypical antidepressants (venlafaxine, mirtazapine, nefazodone)

Placebo

OutcomesRemission, response to treatment, symptom levels, clinical improvement, severity of illness, functional status, adverse events, suicidality, discontinuation from treatment for any reason

7.4.3. Studies considered15

The review team conducted a new systematic search for RCTs that assessed the efficacy and/or safety of antidepressant drugs for children and adolescents with depression.

Twenty-six trials met the eligibility criteria set by the GDG, providing data on 3874 participants. Of these, nine were unpublished trials reviewed by the CSM (CSM, 2003) or FDA (Hammad, 2004), and the remainder were published in peer-reviewed journals between 1987 and 2004. In addition, 37 other studies were excluded from the analysis. The most common reason for exclusion was that there was no control group (further information about both included and excluded studies can be found in Appendix S on CD-ROM).

Of the 26 included trials, there were eight involving a comparison of a tricyclic antidepressant with placebo, 17 involving a comparison of an SSRI/atypical antidepressant with placebo, two involving a comparison of an SSRI with a tricyclic antidepressant, and one involving a comparison of a reversible monoamine oxidase inhibitors (MAOI) with placebo. Of the trials involving a SSRI, there were four published trials of fluoxetine, one published and two unpublished trials of paroxetine, two trials of sertraline (published in one paper using a combined analysis), and one published and one unpublished trial of citalopram (Table 15). Of the trials involving a comparison of an atypical antidepressant with placebo, there was one published and two unpublished trials of venlafaxine, two unpublished trials of mirtazapine, and two unpublished trials of nefazodone (Table 16). Of the trials involving a comparison of an SSRI with a tricyclic antidepressant, there were two published trials of paroxetine versus clomipramine or imipramine (Table 16).

Table 15. Study information for tricyclic antidepressants and individual SSRIs versus placebo.

Table 15

Study information for tricyclic antidepressants and individual SSRIs versus placebo.

Table 16. Study information for atypical antidepressants versus placebo and SSRIs versus tricyclic antidepressants.

Table 16

Study information for atypical antidepressants versus placebo and SSRIs versus tricyclic antidepressants.

7.4.4. Tricyclic antidepressants and individual SSRIs versus placebo

Table 17 summarises both benefits and harms of tricyclic antidepressants and individual SSRIs versus placebo (full results can be found in Appendix S on CD-ROM).

Table 17. Evidence summary table for tricyclic antidepressants and individual SSRIs versus placebo.

Table 17

Evidence summary table for tricyclic antidepressants and individual SSRIs versus placebo.

For individual SSRIs, treatment-emergent adverse events reported by 5% or more of the patients treated with the active drug are displayed in Figure 4 to Figure 8.

Figure 4. Treatment-emergent adverse events in patients taking fluoxetine or placebo: pooled placebo-controlled data.

Figure 4

Treatment-emergent adverse events in patients taking fluoxetine or placebo: pooled placebo-controlled data.

Figure 5. Treatment-emergent adverse events in patients taking paroxetine or placebo: pooled placebo-controlled data.

Figure 5

Treatment-emergent adverse events in patients taking paroxetine or placebo: pooled placebo-controlled data.

Figure 6. Treatment-emergent adverse events in patients (6–11 years) taking sertraline or placebo: pooled placebo-controlled data.

Figure 6

Treatment-emergent adverse events in patients (6–11 years) taking sertraline or placebo: pooled placebo-controlled data.

Figure 7. Treatment-emergent adverse events in patients (12–17 years) taking sertraline or placebo: pooled placebo-controlled data.

Figure 7

Treatment-emergent adverse events in patients (12–17 years) taking sertraline or placebo: pooled placebo-controlled data.

Figure 8. Treatment-emergent adverse events in patients taking citalopram or placebo: pooled placebo-controlled data (sample size varied depending on adverse event).

Figure 8

Treatment-emergent adverse events in patients taking citalopram or placebo: pooled placebo-controlled data (sample size varied depending on adverse event).

7.4.5. Selective serotonin reuptake inhibitors versus tricyclic and related antidepressants, and atypical antidepressants versus placebo

Table 18 summarises both benefits and harms of SSRIs versus tricyclic antidepressants and venlafaxine/mirtazapine versus placebo (full results can be found in Appendix S on CD-ROM).

Table 18. Evidence summary table for SSRIs versus tricyclic antidepressants, and atypical antidepressants versus placebo.

Table 18

Evidence summary table for SSRIs versus tricyclic antidepressants, and atypical antidepressants versus placebo.

For venlafaxine and mirtazapine, treatment-emergent adverse events reported by 5% or more of the patients treated with the active drug are displayed in Figure 9 and Figure 10.

Figure 9. Treatment-emergent adverse events in patients taking venlafaxine or placebo: pooled placebo-controlled data.

Figure 9

Treatment-emergent adverse events in patients taking venlafaxine or placebo: pooled placebo-controlled data.

Figure 10. Treatment-emergent adverse events in patients taking mirtazapine or placebo: pooled placebo-controlled data.

Figure 10

Treatment-emergent adverse events in patients taking mirtazapine or placebo: pooled placebo-controlled data.

7.4.6. Safety of SSRIs/atypical antidepressants versus placebo

The safety of SSRIs/atypical antidepressants was further assessed by pooling the data on suicidal behaviour/ideation (full results can be found in Appendix S on CD-ROM). When all available data were combined, there was limited evidence that SSRIs/atypical antidepressants increase the risk of suicide behaviour/ideation (3.1% vs. 1.8%; RR = 1.79; 95% CI, 1.15 to 2.79). When data from SSRIs were pooled, there remained limited evidence of an increased risk of suicidal behaviour/ideation (4.1% vs. 2.7%; RR = 1.54; 95% CI, 0.66 to 2.46). When all available data were combined, there was limited evidence that SSRIs/atypical antidepressants increase the risk of early discontinuation of treatment because of adverse events (8.6% vs. 4.8%; RR = 1.79; 95% CI, 1.30 to 2.46).

7.4.7. St John's wort

St John's wort, an extract of the plant hypericum perforatum, has been used for centuries for medicinal purposes including the treatment of depression. However, no RCTs were found that assess the safety or efficacy of St John's wort in children or young people with depression.

It is not licensed as a medicine in the UK but can be bought ‘over the counter’ from health food shops, herbalists and community pharmacies. Many different branded preparations are available. At least 19 studies have been conducted in adults with depression (see adult depression guideline (NICE, 2004) for more information).

St John's wort has been found to interact with several types of prescription drugs and can increase or decrease their effectiveness and may increase the risk of serious adverse effects (Committee on Safety of Medicines, 2000). It may also cause photosensitivity.

7.4.8. Clinical summary

For individual outcomes, the quality of the evidence was generally moderate to low, reflecting the paucity of data and relatively small sample sizes of those studies available. Interpretation of harm-related outcomes, especially suicidality, was often difficult due to the short duration of some trials and because the trials were not necessarily designed to measure harm-related outcomes.

Tricyclic antidepressants

In children and young people, it is unlikely that tricyclic antidepressants have clinically important benefits over placebo for remission, response to treatment (50% reduction in symptoms) or reduction in symptoms.

At least in young people, there is limited evidence that tricyclics produce more side effects than placebo and are more likely to lead to discontinuation of treatment. It is also known that tricyclic antidepressants (except lofepramine) are highly toxic in overdose.

Fluoxetine (SSRI)

Fluoxetine (up to 40 mg/day for 7 to 12 weeks) showed efficacy across a range of outcomes in 7–18 year olds. When compared with placebo, fluoxetine produced clinically important improvement in depressive symptoms (when measured with a clinician completed rating scale) and improved the likelihood of both remission and response to treatment, and had a positive impact regarding general clinical improvement and the severity of depression. Evidence is inconclusive regarding the impact on functional status.

The relative risk of serious adverse events and suicidal behaviour is difficult to interpret because of wide confidence intervals, although the rate of harm-related adverse events and suicidal behaviour/ideation was higher in fluoxetine than placebo-treated patients. However, there is evidence that fluoxetine is less likely than placebo to lead to discontinuation of treatment for any reason.

Treatment-emergent adverse events were generally similar between fluoxetine and placebo with the exception of hyperkinesias, headache and skin rash, where there is evidence suggesting increased risk for fluoxetine.

Paroxetine (SSRI)

In one study, paroxetine (up to 40 mg/day for 8 to 12 weeks) improved the likelihood of remission in 12–18 year olds. However, further evidence suggested paroxetine had little impact on response to treatment, symptom levels, functional status, or clinical improvement.

There is evidence suggesting that paroxetine is more likely than placebo to bring about serious adverse effects, and limited evidence of increased risk of suicidal behaviour/ideation and early discontinuation from treatment because of adverse events or any reason.

Paroxetine is more likely than placebo to cause the following treatment-emergent adverse events: dizziness, hostility, insomnia, somnolence and tremor.

Sertraline (SSRI)

Sertraline (up to 200 mg/day for 10 weeks) when compared with placebo produced a small improvement in depressive symptoms in 6–17 year olds. However, the evidence regarding remission, response to treatment, and clinical improvement is inconclusive. Evidence suggests no impact on functional status.

There is evidence suggesting that children (6–11 years) treated with sertraline are more likely to discontinue treatment because of adverse events, and for children/young people there is limited evidence of increased risk of suicidal behaviour/ideation. Evidence is inconclusive regarding serious adverse events. There is limited evidence for an increased risk of discontinuation of treatment for any reason.

In children (6–11 years), sertraline is more likely than placebo to cause the following treatment-emergent adverse events: nausea, diarrhoea, and anorexia; and may increase the risk of vomiting, agitation, urinary incontinence, and purpura. In young people (12–17 years), sertraline is more likely than placebo to cause vomiting and diarrhoea.

Citalopram (SSRI)

There was limited evidence that citalopram (up to 40 mg/day for 8 to 12 weeks), when compared with placebo, improved the chance of remission and response to treatment, and improved depressive symptoms in 7–18 year olds.

There was limited evidence that citalopram increases the risk of treatment-emergent adverse events, suicidal behaviour/ideation, early discontinuation because of suicide attempts, and early discontinuation because of adverse events.

Citalopram is more likely than placebo to cause the following treatment-emergent adverse events: rhinitis, nausea, flu-like symptoms, fatigue, diarrhoea, and pharyngitis.

Venlafaxine (SNRI)

There was limited evidence suggesting that venlafaxine (up to 225 mg/day for 8 weeks) when compared with placebo produced a small improvement in depressive symptoms in 6–17 year olds. There is no evidence to judge whether venlafaxine improves the likelihood of remission, response to treatment, or functional status.

Evidence suggests venlafaxine increases the risk of suicidal behaviour/ideation and leads to early discontinuation because of adverse events.

There is limited evidence to suggest that venlafaxine is more likely than placebo to cause the following treatment-emergent adverse events: nausea, anorexia and dizziness.

Mirtazapine (presynaptic a2-antagonist)

Evidence is inconclusive regarding the effect of mirtazapine (15–45 mg/day for 8 weeks) when compared with placebo on depressive symptoms in 7–17 year olds. There was no evidence regarding remission, response to treatment, or functional status.

Evidence for increased risk of suicidal behaviour/ideation was inconclusive. There was limited evidence that mirtazapine increases the risk of early discontinuation because of adverse events. Mirtazapine was more likely than placebo to cause the following treatment-emergent adverse events: weight gain, somnolence, headache, and increased appetite.

Pooled safety analysis for the SSRIs and the atypical antidepressants

There is limited evidence that across all available data for the SSRIs and atypical antidepressants, there is an increased risk of suicidal behaviour/ideation. These drugs also increase the risk of early discontinuation because of adverse events. For the SSRIs alone, there is limited evidence of an increased risk of suicidal behaviour/ideation.

SSRIs versus tricyclic antidepressants

Evidence suggests that an SSRI (paroxetine [up to 40 mg/day for 8 weeks]) when compared with a tricyclic antidepressant (imipramine [up to 200 mg/day for 8 weeks]) may increase the likelihood of remission in 12–18 year olds. The evidence is inconclusive regarding response to treatment and depressive symptoms. The evidence is also inconclusive regarding clinical improvement when comparing a SSRI (paroxetine [up to 40 mg/day for 8 weeks]) with tricyclics (imipramine [up to 200 mg/day for 8 weeks] or clomipramine [up to 150 mg/day for 8 weeks]) in 12–20 year olds.

Evidence is inconclusive regarding the risk of suffering adverse events and suggests that paroxetine may have a lower risk of early discontinuation of treatment because of adverse events.

St John's wort

There is no evidence for the use of St John's wort in the treatment of depression in children and young people. However, it may cause problems when used in combination with other prescription medicines.

Conclusion

Fluoxetine is the only SSRI/atypical antidepressant where there is evidence of clinical effectiveness across a range of outcome measures. The evidence suggests that tricyclic antidepressants should not be used. Due to lack of data in young people, the potential for drug interactions and the fact that St John's wort is not a licensed medicine, it should not be prescribed.

There is limited evidence that all SSRIs/atypical antidepressants (including fluoxetine) may increase the risk of suicidal ideation and/or behaviour and increase the risk of discontinuation of treatment because of adverse events.

7.5. Antidepressant drug versus psychological therapies, and the combination

7.5.1. Introduction

Little research has focused on the direct comparison of antidepressants with psychological therapies, or on the combination of these treatments. The most recent trial, conducted by the Treatment for Adolescents With Depression Study (TADS) team, is the largest community sampled trial of depression in young people. The first stage of the study assessed the safety and effectiveness of fluoxetine, CBT, and their combination when compared with placebo in 439 young people (12–17 years) with moderate to severe depression. It is important to note that while the group receiving fluoxetine alone or placebo were blind to treatment, those in the combined treatment group were informed they were receiving fluoxetine, and those receiving CBT were by necessity unblind to treatment.

There is also at least one ongoing study, the Treatment Of Resistant Depression In Adolescents (TORDIA), which aims to recruit 400 boys and girls aged 12–18 years, who are currently prescribed an SSRI, to a 12-week RCT. There are four conditions: (1) switching to an alternative SSRI, (2) switching to a different non-SSRI antidepressant, (3) switching to an alternative SSRI and receiving CBT, or (4) switching to a different non-SSRI antidepressant and receiving CBT. More information can be found through the following website: http://clinicaltrials.gov/show/NCT00018902.

7.5.2. Treatment included

The following treatments were included:

7.5.3. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy of an antidepressant versus a psychological intervention and/or the combination.

One trial (TADS200416) met the eligibility criteria set by the GDG, providing data on 439 participants. TADS2004 randomised participants to fluoxetine alone (n = 109), CBT alone (n = 111), fluoxetine with CBT (n = 107), or placebo (n = 112). The duration of the study was 12 weeks. All participants were diagnosed with major depressive disorder by DSM-IV and were aged 12–17 years. Based on the Children's Depression Rating Scale – Revised (CDRS-R), participants had moderate to severe depression, with 27% having at least minimal suicidal ideation at baseline. Those randomised to fluoxetine alone or placebo were blind to treatment, whereas those receiving the combination of fluoxetine and CBT were not.

A further study (MANDOKI1997), randomised 40 participants with depression aged 8–18 years to venlafaxine with psychotherapy (n = 20) or psychotherapy alone (n = 20). However, this study was excluded from the analysis because it provided no information about the type of psychotherapy used or whether it was manualised.

7.5.4. Fluoxetine alone versus CBT alone

Table 19. Evidence summary table for fluoxetine alone/fluoxetine combined with CBT versus CBT alone/placebo/fluoxetine alone.

Table 19

Evidence summary table for fluoxetine alone/fluoxetine combined with CBT versus CBT alone/placebo/fluoxetine alone.

7.5.5. Clinical summary

For individual outcomes, the quality of the evidence was moderate, reflecting the fact only one study was included in the review.

Fluoxetine alone versus CBT

Fluoxetine (up to 40 mg/day for 12 weeks) alone showed evidence of a reduction in depressive symptoms and limited evidence of global clinical improvement when compared with CBT (15 sessions of between 50 and 60 minutes for 12 weeks) alone.

There is limited evidence favouring CBT in relation to harm-related adverse events, suicide attempts, suicide-related events and suicidal ideation.

Fluoxetine plus CBT versus placebo

There is evidence that fluoxetine (up to 40 mg/day for 12 weeks) in combination with CBT (15 sessions of between 50 and 60 minutes for 12 weeks) reduces depressive symptoms and produces global clinical improvement when compared with placebo.

There is limited evidence that fluoxetine in combination with CBT is more likely to bring about increases in harm-related adverse events, suicide attempts and suicide-related events than placebo. However, this was not confirmed by a self-report measure of suicidal ideation, which suggested no increase in risk.

Fluoxetine plus CBT versus fluoxetine alone

There is limited evidence that fluoxetine in combination with CBT reduces depressive symptoms and produces global clinical improvement when compared with fluoxetine alone.

There is limited evidence that fluoxetine in combination with CBT is less likely to bring about suicide-related events and suicidal ideation but more likely to bring about suicidal attempts. Evidence regarding harm-related adverse events is inconclusive.

Fluoxetine plus CBT versus CBT alone

Fluoxetine in combination with CBT showed evidence of a reduction in depressive symptoms and limited evidence of global clinical improvement when compared with CBT alone.

There is limited evidence that fluoxetine in combination with CBT is more likely to bring about increases in harm-related adverse events, suicide attempts and suicide-related events than CBT alone. There is evidence that fluoxetine in combination with CBT produces no difference in suicidal ideation when compared with CBT alone.

Conclusion

Fluoxetine in combination with CBT is more effective in reducing depressive symptoms and producing global clinical improvement. The effect is strongest when compared with placebo and weakest when compared with fluoxetine alone.

There is limited evidence suggesting that the fluoxetine may increase suicidal ideation and/or behaviour but that the addition of CBT may reduce this risk.

7.6. Other drug treatment

7.6.1. Introduction

There is a paucity of evidence regarding the use of drugs other than antidepressants to treat depression in children and young people. A search of the literature revealed only one RCT that compared lithium with placebo. Lithium is a drug that was first used to treat mania, but is also used to prevent relapse in patients with bipolar disorders or recurrent depression. Lithium has many pharmacological effects and the exact mechanism(s) by which it reduces mania and prevents relapse are unclear.

7.6.2. Treatment included

The following treatment was included:

7.6.3. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy of drugs other than antidepressants for children and adolescents with depression.

One trial (GELLER1998) met the eligibility criteria set by the GDG, providing data on 30 participants. The duration of the study was 10.5 weeks. All participants were diagnosed with major depressive disorder by DSM-III-R and were between the ages of 6–12 years old. All participants had family history predictors of future bipolar disorder. Forty percent also had dysthymia and a significant proportion had comorbid ADHD or an anxiety disorder.

7.6.4. Lithium versus placebo

Evidence reported by GELLER1998 suggests lithium when compared with placebo is unlikely to improve depressive symptoms (K-SADS treatment × time (ANCOVA) covarying for baseline K-SADS was F = 0.01, p = 0.91), or improve general functioning (Child Global Assessment Scale [C-GAS] treatment × time ANCOVA covarying for baseline C-GAS was F = 3.44, p = 0.07). With regard to adverse events, more lithium-treated participants had vomiting (31.3% versus 0%). There is limited evidence that lithium also increased the risk of early discontinuation of treatment because of adverse events (RR = 7.00; 95% CI, 0.41 to 119.46) and early discontinuation for any reason (RR = 10.11; 95% CI, 0.62 to 164.68).

7.6.5. Clinical summary

There is no evidence regarding the effect of lithium on remission or response to treatment. Lithium is unlikely to improve depressive symptoms or general functioning over and above placebo. Evidence suggests lithium may increase vomiting and the risk of early discontinuation from treatment because of adverse events.

7.7. Relapse prevention

A systematic search of the literature identified no RCTs concerning the prevention of relapse of depression in children and/or young people that met the eligibility criteria set by the GDG. A wider search revealed only case series and naturalistic follow-up reports (Birmaher et al., 2002; Garber et al., 1988; Emslie et al., 1998; Pine, 2002). Clinical practice follows adult guidance with recommendations that if young people respond to antidepressant medication they should continue on that treatment for 6 to 12 months, with medication being discontinued at that point if the young person is well. Phased withdrawal over 4 to 6 weeks is often recommended but there is no clear evidence to support this. None of the reports identified presented compelling evidence on treatment strategies for either continuation (how long to continue treatment after a positive response) or maintenance (how to prevent recurrence).

7.8. Electroconvulsive therapy (ECT)

7.8.1. Introduction

Electroconvulsive therapy (ECT) is a controversial treatment, especially when used with young people. However, its use is rare in the UK and, similarly to adults, largely reserved for young people whose depression is resistant to other treatments or in potentially life-threatening situations.

7.8.2. Current practice

ECT is an electrically induced seizure. An electric current is passed briefly through the brain via electrodes applied to the scalp to induce generalised seizure activity. The individual receiving the treatment is placed under general anaesthetic and muscle relaxants are given to prevent body spasms. The ECT electrodes can be placed on both sides of the head (bilateral placement) or on one side of the head (unilateral placement), usually the non-dominant side of the brain.

ECT is used extremely rarely in the UK. Duffett et al., (1999) attempted to survey its use in young people under the age of 18 during one year in 1996. They found 12 young people (aged 12–17 years) who had received ECT, eight of whom had a diagnosis of depression (six with unipolar depression). The total represents a rate of 0.02 per 100,000 total population per year, similar to a 10-year retrospective study in Scotland (Robertson et al., 1997).

7.8.2.1. Indications for use

In 2002 the American Academy of Child and Adolescent Psychiatry (AACAP) published a practice parameter for the use of ECT with adolescents (AACAP, 2002). The following is a summary of the main points relevant to this guideline:

  • The adolescent should be diagnosed with severe, persistent depression, with or without psychotic features
  • The symptoms must be severe, persistent and significantly disabling, including life-threatening symptoms such as refusal to eat or drink, severe suicidality, or florid psychosis
  • Other treatments should have been tried and failed, including at least two or more trials of appropriate psychopharmacology, unless the severity of symptoms precludes waiting for a response to other treatments
  • A psychiatrist experienced in the use of ECT, but not involved in the case should give a second opinion
  • Every adolescent should have a memory assessment before treatment, at the end of treatment and at 3–6 months after treatment
  • The anaesthetist should have experience in the treatment of adolescents
  • Policies should be in place covering consent for the use of ECT with adolescents.

In the UK, Duffett et al., (1999) found that of the eight young people who had a diagnosis of depressive disorder, ECT was used in four as a life-saving intervention and in six due to a failure to respond to medication. In 2003, a NICE health technology appraisal on the use of ECT reported that there was insufficient information to allow appropriate risk–benefit assessment for children and young people, although the risks may be enhanced in this age group.

7.8.3. Studies considered

The review team conducted a new systematic search for RCTs that assessed the efficacy and/or safety of ECT for children and adolescents with depression. However, no controlled trials were found. A wider search for evidence found several reviews of single case studies or case series using variable methodology and variable outcome measures (Baldwin & Oxlad, 1996; Rey & Walter, 1997; Walter et al., 1999a).

7.8.4. Clinical evidence

No controlled trials were found on the use of ECT in young people. Most of the evidence relies on single case studies or case series using variable methodology and variable outcome measures. There is likely to be a publication bias in favour of positive outcomes, especially with single case studies.

Rey and Walter (1997) found 66 reports describing ECT in 396 patients aged 18 years or younger. Baldwin and Oxlad (1996) reviewed 217 cases of ‘minors’ who had received ECT between 1947 and 1996. Search strategies were not reported.

Other reviews and case series considered included much smaller numbers.

7.8.4.1. Efficacy

Walter and colleagues (1999a) reviewed the outcomes of 87 patients with depression who had been treated with ECT aged 18 years or younger. They concluded 58 (67%) had remitted, or showed marked improvement of symptoms after treatment.

Baldwin and Oxlad, in their review of 217 ‘minors’ also suggest positive outcomes for many following ECT, although they have not included depressive disorder as a sub-group within their analysis. Despite generally positive findings, they question the interpretation of this data due to the methodology and publication bias in the published literature. However, Walter and colleagues (1999a) found significant differences between diagnostic categories, in particular, showing that ECT was more effective with depressed young people than for other diagnoses such as schizophrenia. This is suggestive of a real effect for the depressed group, over and above any possible publication bias.

Duffett and colleagues (1999), in their UK case series of 12 under 18 year olds who received ECT during 1996, used the Clinical Global Impression of Change and found five had much, or very much, improved; three had improved; three were unchanged and for one the data was missing. Although this sample is small, it is UK only and avoids the issues of publication bias.

7.8.4.2. Adverse events

The main side effects for young people receiving ECT for depression appear to be the same as for adults. ECT may cause short or long-term memory impairment for past events (retrograde amnesia) and current events (anterograde amnesia). As this type of cognitive impairment is a feature of many mental health problems, including severe depression, it may sometimes be difficult to differentiate the effects of ECT from those associated with the condition itself.

The risks associated with ECT may be enhanced ‘in children and young people, and therefore clinicians should exercise particular caution when considering ECT treatment in [this] group’ (NICE, 2003).

One small study has been published (Cohen et al., 2000) assessing cognitive functioning, in particular memory functioning, in 10 under 19 year olds who had received bilateral ECT an average of 3.5 years previously. Cognitive test scores were similar to those in a comparison group matched for sex, age and diagnosis. Six patients reported subjective memory loss immediately after treatment and one complained of persistent memory loss at follow-up. It is not possible to draw firm conclusions from these findings due to the small numbers and retrospective design.

There are no studies which provide evidence of the impact of ECT on the developing brain.

7.8.4.3. User and parent opinion

Three studies were identified which looked at the views of young people who had received ECT and their parents (Walter et al., 1999b; Walter et al., 1999c and Taieb et al., 2000). Each study used a telephone questionnaire. Walter and colleagues (1999b) used a sample of 26 patients, Walter and colleagues (1999c) sampled 28 parents and Cohen and colleagues (2000) sampled 10 patients and their parents (n = 18).

The views of the young people who had received ECT were mixed, but a small majority believed that ECT was helpful, and more still believed that the effects of their illness were worse than the effects of the ECT. Few young people felt they had any real understanding of the treatment and many expressed a range of fears associated with ECT. Most experienced memory impairment but this largely resolved over time.

Parents were generally as positive, or more positive in their views about ECT, than young people who had received the treatment. Parents were more knowledgeable about what ECT entailed.

7.8.5. Clinical summary

In the UK, ECT is used extremely rarely for the treatment of depression in young people. It is usually reserved for cases where there is a perceived life-threatening situation or where extensive alternative treatments have failed. Without controlled trials, the evidence for efficacy is limited, but case studies and case series suggest it may be of benefit.

The most significant side effect from ECT is memory impairment. The effects of ECT on the developing brain are unknown.

7.9. Psychotic depression

7.9.1. Introduction

Psychotic depression (a major depressive disorder associated with hallucinations and/or delusions) can occur in children and adolescents but has been subject to little systematic study. Pre-pubertal children are more likely to present mostly with auditory hallucinations whilst adolescents may have both delusions and hallucinations. Psychotic depression has been associated with more severe depression, greater long-term morbidity, and higher risk of recurrence, bipolar disorder and suicidality. The presence of psychotic symptoms is suggested to be an indication for the early use of antidepressant medication but also an indication of greater resistance to antidepressant monotherapy (AACAP, 1998.

7.9.2. The management of psychotic depression

Systematic research into depression with psychotic features has been limited by the fact that the disorder is not defined clearly as a distinct diagnostic subtype and because of the difficulties in enrolling such patients in research studies. As a result there are no good quality epidemiological studies and no controlled studies on the acute or longer-term treatment of psychotic depression. A systematic search of electronic databases found only anecdotal reports, case series and best practice guidance from expert bodies. One small study of adolescents has suggested that the combination of antidepressants with antipsychotics may be helpful for patients with psychotic depression (Geller et al., 1985), but this study focused more on plasma drug levels than on outcome measures.

7.10. Clinical practice recommendations

7.10.1. Using antidepressants in children and young people

7.10.1.1.

Antidepressant medication should not be used for the initial treatment of children and young people with mild depression. (B)

7.10.1.2.

The further treatment of children and young people with persisting mild depression unresponsive to treatment at tier 1 or 2 should follow the guidance for moderate to severe depression. (GPP)

7.10.1.3.

Antidepressant medication should not be offered to a child or young person with moderate to severe depression except in combination with a concurrent psychological therapy. Specific arrangements must be made for careful monitoring of adverse drug reactions as well as for reviewing mental state and general progress; for example, weekly contact with the child or young person and their parent(s) or carer(s) for the first 4 weeks of treatment. The precise frequency will need to be decided on an individual basis, and recorded in the notes. In the event that psychological therapies are declined, medication may still be given, but as the young person will not be reviewed at psychological therapy sessions, the prescribing doctor should closely monitor the child or young person's progress on a regular basis and focus particularly on emergent adverse drug reactions. (B)

7.10.1.4.

If an antidepressant is to be prescribed this should only be following assessment and diagnosis by a child and adolescent psychiatrist. (C)

7.10.1.5.

When an antidepressant is prescribed to a child or young person with moderate to severe depression, it should be fluoxetine as this is the only antidepressant for which clinical trial evidence shows that the benefits outweigh the risks. (A)

7.10.1.6.

If a child or young person is started on antidepressant medication, they (and their parent(s) or carer(s) as appropriate) should be informed about the rationale for the drug treatment, the delay in onset of effect, the time course of treatment, the possible side effects, and the need to take the medication as prescribed. Discussion of these issues should be supplemented by written information appropriate to the child or young person's and parents' or carer's needs that covers the issues described above and includes the latest patient information advice from the relevant regulatory authority. (GPP)

7.10.1.7.

A child or young person prescribed an antidepressant should be closely monitored for the appearance of suicidal behaviour, self-harm or hostility, particularly at the beginning of treatment, by the prescribing doctor and the healthcare professional delivering the psychological therapy. Unless it is felt that medication needs to be started immediately, symptoms that might be subsequently interpreted as side effects should be monitored for 7 days before prescribing. Once medication is started the patient and their parent(s) or carer(s) should be informed that if there is any sign of new symptoms of these kinds, urgent contact should be made with the prescribing doctor. (GPP)

7.10.1.8.

When fluoxetine is prescribed for a child or young person with depression, the starting dose should be 10 mg daily. This can be increased to 20 mg daily after 1 week if clinically necessary, although lower doses should be considered in children of lower body weight. There is little evidence regarding the effectiveness of doses higher than 20 mg daily. However, higher doses may be considered in older children of higher body weight and/or when, in severe illness an early clinical response is considered a priority. (GPP)

7.10.1.9.

When an antidepressant is prescribed in the treatment of a child or young person with depression and a self-report rating scale is used as an adjunct to clinical judgement this should be a recognised scale such as the Mood and Feelings Questionnaire (MFQ). (GPP)

7.10.1.10.

When a child or young person responds to treatment with fluoxetine, medication should be continued for at least 6 months after remission (defined as no symptoms and full functioning for at least 8 weeks); in other words for 6 months after this 8-week period. (C)

7.10.1.11.

If treatment with fluoxetine is unsuccessful or is not tolerated because of side effects, consideration should be given to the use of another antidepressant. In this case sertraline or citalopram are the recommended second-line treatments. (B)

7.10.1.12.

Sertraline or citalopram should only be used when the following criteria have been met:

  • The child or young person and their parent(s) or carer(s) have been fully involved in discussions about the likely benefits and risks of the new treatment and have been provided with appropriate written information. This information should cover the rationale for the drug treatment, the delay in onset of effect, the time course of treatment, the possible side effects, and the need to take the medication as prescribed; it should also include the latest patient information advice from the relevant regulatory authority
  • The child or young person's depression is sufficiently severe and/or causing sufficiently serious symptoms (such as weight loss or suicidal behaviour) to justify a trial of another antidepressant
  • There is clear evidence that there has been a fair trial of the combination of fluoxetine and a psychological therapy (in other words that all efforts have been made to ensure adherence to the recommended treatment regimen)
  • There has been a reassessment of the likely causes of the depression and of treatment resistance (for example other diagnoses such as bipolar disorder or substance abuse)
  • There has been advice from a senior child and adolescent psychiatrist – usually a consultant.
  • The child or young person and/or someone with parental responsibility for the child or young person (or the young person alone, if over 16 or deemed competent) has signed an appropriate and valid consent form. (C)
7.10.1.13.

When an antidepressant other than fluoxetine is prescribed for a child or young person with depression, the starting dose should be half the daily starting dose for adults. This can be gradually increased to the daily dose for adults over the next 2 to 4 weeks if clinically necessary, although lower doses should be considered in children with lower body weight. There is little evidence regarding the effectiveness of the upper daily doses for adults in children and young people, but these may be considered in older children of higher body weight and/or when, in severe illness, an early clinical response is considered a priority. (GPP)

7.10.1.14.

When a child or young person responds to treatment with citalopram or sertraline, medication should be continued for at least 6 months after remission (defined as no symptoms and full functioning for at least 8 weeks). (C)

7.10.1.15.

Paroxetine and venlafaxine should not be used for the treatment of depression in children and young people. (A)

7.10.1.16.

Tricyclic antidepressants should not be used in the treatment of depression in children and young people. (C)

7.10.1.17.

Where antidepressant medication is to be discontinued, the drug should be phased out over a period of 6 to 12 weeks with the exact dose being titrated against the level of discontinuation/withdrawal symptoms. (C)

7.10.1.18.

As with all other medications, consideration should be given to possible drug interactions when prescribing medication for depression in children and young people. This should include possible interactions with complementary and alternative medicines as well as with alcohol and ‘recreational’ drugs. (GPP)

7.10.1.19.

Although there is some evidence that St John's wort may be of some benefit in adults with mild to moderate depression, this cannot be assumed for children or young people, for whom there are no trials upon which to make a clinical decision. Moreover, it has an unknown side-effect profile and is known to interact with a number of other drugs, including contraceptives. Therefore St John's wort should not be prescribed for the treatment of depression in children and young people. (C)

7.10.1.20.

A child or young person with depression who is taking St John's wort as an over-the-counter preparation should be informed of the risks and advised to discontinue treatment while being monitored for recurrence of depression and assessed for alternative treatments in accordance with this guideline. (C)

7.10.2. Antidepressants combined with psychological treatments

7.10.2.1.

If moderate to severe depression in a child or young person is unresponsive to psychological therapy after four to six treatment sessions, a multidisciplinary review should be carried out. (GPP)

7.10.2.2.

Following multidisciplinary review, if the child or young person's depression is not responding to psychological therapy as a result of other coexisting factors such as the presence of comorbid conditions, persisting psychosocial risk factors such as family discord, or the presence of parental mental il-health, alternative or perhaps additional psychological therapy for the parent or other family members, or alternative psychological therapy for the patient, should be considered. (C)

7.10.2.3.

Following multidisciplinary review, if moderate to severe depression in a young person (12–18 years) is unresponsive to a specific psychological therapy after four to six sessions, fluoxetine should be offered. (B)

7.10.2.4.

Following multidisciplinary review, if moderate to severe depression in a child (5–11 years) is unresponsive to a specific psychological therapy after four to six sessions, the addition of fluoxetine should be cautiously considered, although the evidence for its effectiveness in this age group is not established. (C)

7.10.2.5.

If moderate to severe depression in a child or young person is unresponsive to combined treatment with a specific psychological therapy and fluoxetine after a further six sessions, or the patient and/or their parent(s) or carer(s) have declined the offer of fluoxetine, the multidisciplinary team should make a full needs and risk assessment. This should include a review of the diagnosis, examination of the possibility of comorbid diagnoses, reassessment of the possible individual, family and social causes of depression, consideration of whether there has been a fair trial of treatment, and assessment for further psychological therapy for the patient and/or additional help for the family. (GPP)

7.10.3. Discharge after first episode

7.10.3.1.

When a child or young person is in remission (less than two symptoms and full functioning for at least 8 weeks) they should be reviewed regularly for 12 months by an experienced CAMHS professional. The exact frequency of contact should be agreed between the CAMHS professional and the child or young person and/or the parent(s) or carer(s) and recorded in the notes. At the end of this period, if remission is maintained, the young person can be discharged to primary care. (C)

7.10.3.2.

CAMHS should keep primary care professionals up to date about progress and the need for monitoring of the child or young person in primary care. CAMHS should also inform relevant primary care professionals within 2 weeks of a patient being discharged and should provide advice about whom to contact in the event of a recurrence of depressive symptoms. (GPP)

7.10.3.3.

Children and young people who have been successfully treated and discharged but then re-referred should be seen as soon as possible rather than placed on a routine waiting list. (GPP)

7.10.4. Recurrent depression and relapse prevention

7.10.4.1.

Specific follow-up psychological therapy sessions to reduce the likelihood of, or at least detect, a recurrence of depression should be considered for children and young people who are at a high risk of relapse (for example, individuals who have already experienced two prior episodes, those individuals who have high levels of subsyndromal symptoms, or those who remain exposed to multiple-risk circumstances). (B)

7.10.4.2.

CAMHS specialists should teach recognition of illness features, early warning signs, and subthreshold disorders to tier 1 professionals, children or young people with recurrent depression and their families and carer(s). Self-management techniques may help individuals to avoid and/or cope with trigger factors. (GPP)

7.10.4.3.

When a child or young person with recurrent depression is in remission (less than two symptoms and full functioning for at least 8 weeks) they should be reviewed regularly for 24 months by an experienced CAMHS professional. The exact frequency of contact should be agreed between the CAMHS professional and the child or young person and/or the parent(s) or carer(s) and recorded in the notes. At the end of this period, if remission is maintained, the young person can be discharged to primary care. (C)

7.10.4.4.

Children and young people with recurrent depression who have been successfully treated and discharged but then re-referred should be seen as a matter of urgency. (GPP)

7.10.5. Electroconvulsive therapy

7.10.5.1.

ECT should only be considered for young people with very severe depression and either life-threatening symptoms (such as suicidal behaviour) or intractable and severe symptoms that have not responded to other treatments. (C)

7.10.5.2.

ECT should be used extremely rarely in young people and only after careful assessment by a practitioner experienced in its use and only in a specialist environment in accordance with NICE recommendations. (C)

7.10.5.3.

ECT is not recommended in the treatment of depression in children (5–11 years). (C)

7.10.6. Pharmacological management of psychotic depression

7.10.6.1.

For children and young people with psychotic depression, augmenting the current treatment plan with an atypical antipsychotic medication should be considered, although the optimum dose and duration of treatment are unknown. (C)

7.10.6.2.

Children and young people prescribed an atypical antipsychotic medication should be monitored carefully for side effects. (C)

Footnotes

13
14
15

Here and elsewhere in the guideline, each study considered for review is referred to by a study ID (primary author and date of study publication, except where a study is in press or only submitted for publication, then a date is not used).

16

This study was also included in the analysis of antidepressants versus placebo and the analysis of CBT versus non-directive supportive therapy or clinical management.

Copyright © 2005, The British Psychological Society & The Royal College of Psychiatrists.

All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Enquiries in this regard should be directed to the British Psychological Society.

Cover of Depression in Children and Young People
Depression in Children and Young People: Identification and Management in Primary, Community and Secondary Care.
NICE Clinical Guidelines, No. 28.
National Collaborating Centre for Mental Health (UK).
Leicester (UK): British Psychological Society; 2005.

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