Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are the best studied antidepressant medications for children and adolescents. They also have significant benefit for anxiety disorders including Generalized Anxiety Disorder, Panic Disorder, and OCD. The effects of SSRIs upon anxiety are important given that anxiety is commonly comorbid with depression.
SSRI side effects are usually mild and often transient. Common side effects include: headaches, GI upset, somnolence, agitation, and sexual side effects (e.g. decreased libido, anorgasmia).
In both adults and children SSRIs confer a small risk of serotonin syndrome, which is an adverse reaction and a medical emergency. Symptoms of serotonin syndrome include fever, confusion, and tremor/rigidity. Risk is increased by certain medication interactions. The most significant and dangerous medication interaction for SSRIs is with MAOIs (monoamine oxidase inhibitors – another type of antidepressant which is infrequently used in children). All patients should be questioned about other medications they are taking, including herbal and OTC medications. If serotonin syndrome is suspected in a patient, SSRI should be immediately discontinued and the patient should be referred to an emergency room for hospital admission. Treatment is supportive.
- Fluoxetine (Prozac ®): Fluoxetine has the most positive data from controlled trial in children and adolescents with 3 trials demonstrating significant difference from placebo. [March: 2004], [Emslie: 2002], [Emslie: 1997] It also has FDA approval for use in children ages 7 to 18 with Major Depressive Disorder. Fluoxetine has a longer half-life than most other SSRIs (1 to 4 days) and an active metabolite, norfluoxetine, which has an even longer half-life (7 to 15 days). This can be a useful pharmacokinetic feature as it is somewhat more forgiving than other SSRIs when doses are missed. However, if a patient has an adverse reaction to fluoxetine, the long half-life can extend the duration of such a reaction. Starting dose for adolescents: 10 to 20mg once daily, initial target dose 20mg once daily, dose range 10mg to 60mg once daily.
- Sertraline (Zoloft ®): Sertraline has one positive trial (two studies, which were combined by study design), however the significance of the trial results was lessened by very high placebo response rate (53%). [Wagner: 2003] High placebo response rates are characteristic of all existing trials of antidepressants in children and adolescents. Starting dose for adolescents: 12.5mg to 25mg once daily, initial target dose 50mg once daily, dose range 25mg to 200mg once daily.
- Paroxetine (Paxil ®, Paxil CR ®): Paroxetine has one trial with mixed results [Keller: 2001] and one negative trial (unpublished, see [Cheung: 2005]), so the evidence for efficacy is equivocal. Paroxetine also appears to be less well tolerated in children and adolescents in this author’s opinion, and has significant discontinuation symptoms (possibly due to short half life of 20 hours). Other SSRIs may be better choices for children and adolescents.
- Citalopram (Celexa ®): Citalopram has had two controlled trials. One had positive results [Wagner: 2004] and the other did not show significant difference from placebo (unpublished). The non-significant study included inpatients and also had a high dropout rate, which may have made the results difficult to interpret. Citalopram has also been studied in pediatric patients with functional abdominal pain. In August 2011, the FDA issued a Drug Safety Communication warning of the potential for QT prolongation and Torsades de Pointes in patients taking citalopram at doses higher than 40mg daily, and stated that citalopram shoud no longer be used at doses higher than 40mg daily. The FDA also discouraged use of citalopram at any dose in patients with certain cardiac conditions predisposing to arrhythmia, including congenital long QT syndrome. Starting dose for adolescents: 10mg once daily, initial target dose 10mg to 20mg once daily, dose range 10mg to 40mg once daily.
- Escitalopram (Lexapro ®): Escitalopram is the S-isomer of citalopram. Escitalopram has had 3 controlled trials. One controlled trial in adolescents aged 12 to 17 years had positive results (unpublished data, Forest Laboratories). Two other controlled trials ([Wagner: 2006] and unpublished data, Forest), did not show significant difference from placebo. Of note, a post-hoc analysis of the data from the published negative study showed a significant difference from placebo for the adolescent age group. On the strength of the positive study and data from a positive study of citalopram, escitalopram was recently granted FDA approval for treatment of depression in adolescents aged 12 to 17 years. Starting dose for adolescents: 5mg to 10mg once daily, initial target dose 10mg once daily, dose range 10mg to 30mg once daily.
Tricyclic Antidepressants Tricyclic antidepressants (TCAs)
TCAs have been available for many years but have been eclipsed by the SSRIs, largely due to the SSRIs having fewer side effects and less toxicity. It is important for pediatric providers to know that multiple trials of TCAs have failed to show significant benefit compared to placebo for treatment of depression in children and adolescents.
Other Non-SSRI Antidepressants
- Bupropion (Wellbutrin ®, Wellbutrin SR®, Wellbutrin XL®, Zyban ®). There are no controlled studies of bupropion for depression in children and adolescents. There is one open study of bupropion in children with depression and comorbid ADHD that has positive results. [Daviss: 2001] Bupropion is used in adults for depression and smoking cessation. Unlike SSRIs, bupropion has little effect on anxiety. It may be useful in patients with Bipolar Disorder and depression as it is less likely than other antidepressants to induce mania. There is a small risk of generalized seizures with bupropion, which is higher at doses greater than 300mg daily. Due to increased risk of seizures, bupropion is contraindicated in patients with an active eating disorder. Starting doses in adolescents: bupropion SR 75mg twice daily, initial target dose 100mg twice daily, dose range 75mg to 150mg twice daily; bupropion XL (Wellbutrin XL ®) starting dose 150mg once daily, initial target dose 150mg to 300mg once daily, dose range 150mg to 450mg once daily.
- Venlafaxine (Effexor ®, Effexor XR ®): Venlafaxine is an SNRI (serotonin-norepinephrine reuptake inhibitor) and thus possesses an additional mechanism of action compared with SSRIs. The spectrum of effects of venlafaxine is nonetheless similar to that of the SSRIs. In fact, at lower doses (less than 225 mg daily) the norepinephrine reuptake action is not present, effectively making venlafaxine an SSRI at these doses. There have been few studies of its use in children and adolescents. Venlafaxine was studied in a large RCT involving patients who continued to have depression despite adequate treatment with one SSRI, and was not significantly better in that context than a second SSRI; there was no placebo arm. [Brent: 2008] One unpublished study and one small, randomized controlled trial did not show significant benefits [Boylan: 2007] Pooled results of these two studies showed a small benefit for adolescents only. Studies may have been hampered by a high rate of placebo response. Venlafaxine also has significant discontinuation symptoms that may begin within a few hours of a missed dose. For these reasons, venlafaxine is at best a second line medication for children and adolescents with depression.
- Mirtazapine (Remeron ®): Mirtazapine is also considered an SNRI, although it has other actions at the CNS receptor level that may also contribute to antidepressant effect. There have been two unpublished trials of mirtazapine for depression in children and adolescents.Neither trial demonstrated significant difference from placebo. Like with venlafaxine, this lack of apparent effect may be due to high placebo response rates. Still, mirtazapine would not be a first line medication choice for children and adolescents with depression.
- Duloxetine (Cymbalta ®): There has been one open label trial of duloxetine with children and adolescents, looking primarily at safety and tolerability. [Prakash: 2012] Until more positive findings are produced, duloxetine would not be a first line medication for children and adolescents with depression.
- Levomilnacipran (Fetzima ®): The newest SNRI on the market, just approved by FDA for treatment of depression in adults in July 2013. No studies in children or adolescents.
Use of antidepressant medication in children has become a controversial topic ever since the British Medications and Healthcare Regulatory Agency banned the use of all antidepressants with the exception of fluoxetine in patients less than 18 years of age in the United Kingdom. This ban was instituted due to concerns about the potential for suicidal thoughts or behavior in patients taking antidepressant medication. Subsequent evaluation of this question by the U.S. FDA led to institution of a black box warning for all antidepressants stating that they may increase the risk of suicidal thinking and behavior in children and adolescents with Major Depressive Disorder and other psychiatric disorders. No antidepressant is exempt from this warning. The FDA is now examining data and considering a similar warning for antidepressant use in adults.
It should be noted that the FDA did not institute a ban on use of antidepressants in children and adolescents, nor did the agency revoke the approval of fluoxetine for treatment of depression in patients aged 7 to 18.
An independent review of available data by the AMA (American Medical Association Report 2005: Safety and Efficacy of Selective Serotonin Reuptake Inhibitors (SSRIs) in Children and Adolescents) indicated that “a causal role for antidepressants in increasing suicides in children and adolescents has not been established.” It went on to state that the “concerns that antidepressants potentiate suicidal or self-injurious behavior need to be balanced by the clear risk of suicide in children and adolescents with untreated depression.” A more recent analysis of all available antidepressant RCTS in youth suggests that antidepressants have benefits that may outweigh these risks. [Bridge: 2007] There is also data demonstrating a correlation between higher rates of SSRI prescriptions and reduction in child and adolescent suicide rates [Gibbons: 2006].
Given concerns for SAEs, rational prescribing practices include making patients and parents aware of the safety concerns around antidepressant use. Patients who are started on antidepressant medication should be observed closely for clinical worsening, suicidal thoughts, or unusual changes in behavior. Families and caregivers should be advised to closely observe the patient and to communicate with the prescribing physician. Follow up should occur within one week after a patient is newly started on an antidepressant.
|Author:||Thomas G. Conover, MD - 12/2009|
|Compiled and edited by:||Catherine Jolma, MD - 12/2009|
|Content Last Updated:||9/2013|
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