Emerging treatments

Transcranial magnetic stimulation (TMS)

There is emerging evidence that repetitive TMS (rTMS) maybe safe and effective for treating depression in adolescents.[149][150]

Vagus nerve stimulation (VNS)

There is evidence to support the use of VNS in adult treatment-resistant depression.[151][152][153] However, there have been no trials for paediatric depression. Because of the invasive nature of the procedure and potential adverse effects, it is not recommended for use in treating paediatric depression.

Transdermal selegiline

Because of the adverse effects and the difficulty of managing diet in children and adolescents, monoamine oxidase inhibitors have not been recommended for use in paediatric depression. However, the transdermal patch formulation of selegiline may bypass the concern and become an alternative treatment for young people with depression resistant to other treatment. One study comparing the selegiline patch and placebo in adolescents with major depression disorder demonstrated safety of the active medication, although response rates were similar for both groups (58.6% versus 59.3%).[132]


Ketamine is a glutamate receptor N-methyl-D-aspartate antagonist, and has been investigated for its antidepressant effect. Glutamate is thought to play an important role in cellular plasticity and resilience.[154] Ketamine has been found to induce a rapid antidepressant response (within hours) in treatment-resistant depression in adults. A study of 18 treatment-resistant depressed adults found a rapid and sustained (1-2 week) antidepressant effect.[155] No paediatric studies have been conducted, but the results from adult studies are promising. The long-term safety and efficacy of ketamine in adults (and by extension in children) remains unclear.[156] A systematic review of 60 articles looking at side effects in adults with depression treated with single and repeated doses of ketamine found that acute side effects were common, and were more likely to occur in patients given intravenous ketamine. The majority of side effects resolved shortly after drug administration. They included psychiatric (most commonly anxiety), psychotomimetic, cardiovascular, and neurological effects. The most common reported effects were headache, dizziness, dissociation, raised blood pressure, and blurred vision. The authors note that insufficient data were available regarding the risks associated with repeated dosing, and that more data are needed on the potential cumulative and long-term risks in patients with depression requiring repeated doses of ketamine over a long period of time. Repeated use of ketamine in other patient groups has been linked to urological and liver toxicity, cognitive deficits, and dependency. Ketamine dependency is a known disorder.[157] The experimental nature of ketamine dosing, the potential for increased suicide risk, and unknown long-term effects should be considered, particularly in the population for which this medication is often indicated: vulnerable patients at risk for death from suicide.

New drug development

Medications targeting different systems (other than serotonin or noradrenaline [norepinephrine]) have been investigated. Studies have found that agomelatine (a melatonin receptor agonist and serotonin 2c receptor antagonist) surpassed placebo[158] and fluoxetine[159] in reducing depression severity and improving sleep, and sertraline in regulating the circadian rest-activity, sleep-wake cycle, and in reducing depressive and anxiety symptoms[160] and preventing relapse in depressed adults.[161]


A meta-analyses has suggested that exercise is effective in treating major depressive disorder in adults,[162] and several trials are under way to assess the efficacy of exercise in treating paediatric depression.

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