SSRIs

SSRIs increase serotonin levels by inhibiting the serotonin transporter and by decreasing reuptake into presynaptic neurons, leaving more serotonin in the synaptic cleft.

Food and Drug Administration (FDA) approvals

FDA approval for serotonin reuptake inhibitors in children and adolescents has been for treatment of OCD and depression. There are no SSRIs with an FDA indication for non-OCD anxiety. Duloxetine, an SNRI, has FDA approval for treatment of GAD in children aged 7 and up.

FDA approvals for treatment of depression

• Fluoxetine (Prozac) >= 8 years of age
• Escitalopram (Lexapro) >= 12 years of age

FDA approvals for Obsessive Compulsive Disorder (OCD)

• Fluvoxamine (Luvox) >= 8 years of age
• Fluoxetine (Prozac) >= 7 years of age
• Sertraline (Zoloft) >= 6 years of age

Evidence for SSRIs in the treatment of mental health disorders in children and adolescents

See the disorders sections for the results of randomized, placebo-controlled trials of SSRIs in the treatment of anxiety and depression in children and adolescents.

The medications with the best evidence base for efficacy and tolerability in the treatment of pediatric anxiety and depression are fluoxetine, sertraline and escitalopram.  These 3 medications are appropriate for use in primary care.

Dosing strategies in prescribing SSRIs in children and adolescents should move patients toward symptom remission while monitoring for treatment-emergent activation or other adverse effects, discussed below. 

The general rule in pediatric prescribing has been “Start low, go slow”, but a more effective strategy is to start low and titrate assertively as tolerated.

Clinical trials of SSRIs have shown that children and adolescents who have symptom response to a given dose of medication will have that response early, with a statistically significant difference by 2 weeks and clinically significant difference by 6 weeks (Strawn, Mills, Sauley, & Welge, 2018). 

This means that dose titration should occur in 3-4 weeks if a patient is tolerating a dose of medication but not demonstrating a significant symptom reduction.

Common, Early, Transient Adverse Effects

Gastrointestinal discomfort, nausea, and diarrhea are common in the first few weeks of treatment and generally resolve. These symptoms are also common among patients with anxiety and depression so baseline symptom assessment can help distinguish treatment-emergent symptoms from increased awareness of baseline symptoms.

Tiredness or insomnia: SSRIs are generally dosed in the morning but if a patient experiences either tiredness or insomnia with an SSRI start, try dosing in the evening.

Less Common Side Effects Over the Course of Treatment

• Easy bruising or bleeding – generally mild
• Excessive sweating
• Sexual side effects: SSRIs are associated with decreased sexual arousal and decreased intensity or duration of orgasm. Discuss this with your adolescent patients as it may be a cause for concern or medication discontinuation. Treatment with a non-SSRI antidepressant may be preferable although less evidence based.

Activation

Activation is an antidepressant treatment-emergent adverse effect manifested as increased activity, irritability, restlessness, disinhibition, impulsivity or insomnia. Activation emerges early in the first few weeks of treatment or after a dosage change. Activation may be associated with increased risk for aggressive behavior or suicide. Antidepressant-related activation is more common in children than in adolescents. Activation is more common with SSRIs as a class than SNRIs as a class (Mills & Strawn, 2019). 

The likelihood of activation may be reduced by initiating antidepressant treatment at low doses, particularly in younger patients and in those with a family history of bipolar disorder. Antidepressant-related activation resolves when the dose is reduced or discontinued. 

Suicidal Ideation

In 2004, after a meta-analysis of 24 placebo-controlled trials assessing use of antidepressant medications among more than 4,400 children and adolescents, the US Food and Drug Administration (FDA) concluded that these medications pose a 2-fold (4% vs. 2%) increased risk for “suicidal behavior or suicidal ideation,” although no completed suicides were reported (Hammad, Laughren, & Racoosin, 2006).

The FDA required the insertion of a black box warning on the labels of all antidepressants indicating an increased risk of suicidal thoughts and behavior in young people taking these medications.  

A 2007 meta-analysis of relative risk for suicidal ideation among pediatric SSRI medication trials evaluated suicide risk in 3 diagnostic groups: major depression (MDD, 15 trials), obsessive compulsive disorder (OCD, 6 trials) and non-OCD anxiety disorders (6 trials). While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs. placebo (0.7%; 95% CI, 0.1%-1.3%), the pooled risk differences within each indication were not statistically significant. There were no completed suicides (Bridge et al., 2007). 

In addressing the black box warning with patients and families prior to medication start, we recommend that clinicians

• review the warning, noting that risk is low but present
• assess history of or baseline suicidal ideation
• have the patient identify a trusted adult with whom they would share suicidal thoughts if they should occur.

No regular laboratory monitoring is indicated in the use of SSRIs. 

While weight gain or loss is not generally significant with the SSRIs discussed in this section, regular monitoring of height, weight, and vital signs is appropriate for all pediatric patients.

CYP 450 System

Fluoxetine and paroxetine are potent CYP2D6 inhibitors, whereas fluoxetine's main metabolite, norfluoxetine, has a moderate inhibitory effect on CYP3A4.

The inhibitory effects on CYP-activity can persist for several weeks after fluoxetine discontinuation because of the long half-life of fluoxetine and its metabolite norfluoxetine.

Sertraline is a moderate CYP2D6 inhibitor.

Drug combinations with SSRIs should be assessed on an individual basis. 

Serotonin Syndrome

Serotonin syndrome is caused by elevated serotonin levels in the central and peripheral nervous systems.

The classic presentation is the triad of autonomic dysfunction, neuromuscular excitation, and altered mental status. 

These symptoms vary based on the severity of serotonergic toxicity and often do not present simultaneously.

The list of drugs potentially causing serotonin syndrome is long, but only MAOIs, SSRIs, SNRIs, and serotonin releasers (fenfluramine, amphetamines, and methylenedioxymethamphetamine (ecstasy) have been reliably confirmed to precipitate serotonin syndrome.

Initiation Phase

Starting the medication, addressing early, generally transient side effects, and titrating to an effective dose. 

Disorder-specific scales can help assess treatment response.

Monthly visits are generally appropriate with more frequent phone check-ins if symptoms are concerning

Maintenance Phase

Once at an effective dose, SSRI treatment for depression or anxiety should continue for the better part of a year.  See below for discontinuation. If symptoms recur or worsen during the maintenance phase, a dose adjustment may occur.

Continuation Phase

Most children and adolescents treated with an SSRI warrant a trial off about a year of stability on the medication. In some young people, more extended treatment is appropriate. These include youth who have had recurrent episodes of major depression, or who have fully relapsed after discontinuation of a medication.  These patients may require several years of treatment.  There is no evidence for adverse effects with long-term SSRI use.

The best time for SSRI discontinuation is when relapse is less likely, which for most children and adolescents means a low-stress period, such as summertime. 

There are little data on rates of adverse effects of SSRI discontinuation in pediatric patients. Most do well with a taper of 25% to 33% of the maintenance dose every 7-10 days until off completely. Fluoxetine can be discontinued without a taper as its long half-life provides an auto-taper. If a patient experiences discontinuation symptoms with a taper, they can return to the dose at which they were asymptomatic and decrease more slowly or by smaller increments.

See Does my patient still need this medication? Discontinuing SSRIs <need link here>.

If a patient does not reach symptom remission at robust dosing (i.e., upper range of typical daily dose in table) of an SSRI for 6 weeks, consider switching to an alternate SSRI (see algorithms). Switching SSRIs can be done by cross tapering over 2-3 weeks.

Antidepressants: Pediatric Mental Health Minute Series

Antidepressants Side Effects: Pediatric Mental Health Minute Series

How to talk with patients and families about SSRIs (RAMP content) (Mini-lesson)

Does my patient still need this medication?  Discontinuing SSRIs (RAMP content) (Mini-lesson)