Antidepressants

https://en.wikipedia.org/wiki/Drug

Background

Modern antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have enjoyed widespread adoption and success in treating a variety of psychiatric conditions in adult populations, but their use in pediatric patients has been fraught with controversy. Although the list of available SSRIs and SNRIs is quite long, the FDA has only approved one, fluoxetine, for use in the treatment of depression in children ages 8 and older, though many others are often used off-label. One reason for lack of FDA approval is the fact that there have been few randomized controlled trials to study these drugs in children. The controversy surrounding antidepressant use in pediatric patients dates to 2004 when the FDA directed manufacturers of all antidepressant drugs to include warning statements regarding an “increased risk of suicidality (suicidal thinking and behavior) in children and adolescents.” This statement was based on a review of 24 trials with over 4,000 cases, which appeared to demonstrate a two-fold increase in suicidal ideation in “the first few months” of treating adolescents with SSRIs. Importantly, no suicides occurred in any of the reviewed trials. The veracity and magnitude of this assertion has remained an open and actively studied question, with many papers published to support all sides of the debate. The question is a hard one both scientifically and politically. Even in depressed pediatric patients, suicide is a rare event, which makes it hard to study. Additionally, there are major confounding aspects to consider when suicidality in the face of depression is the outcome of interest. Perhaps those who received SSRIs are simply more willing to discuss the same feelings they were having prior to treatment?

Despite the difficulties of researching these questions, some degree of consensus has begun to emerge. The findings from the Treatment for Adolescents and Depression Study (TADS), completed in 2009, were that SSRIs were effective with a number needed to treat of 4. A Cochrane review surveying the literature as it stood in 2012 concluded that “If a decision to use medication is agreed then fluoxetine might be the medication of first choice given guideline recommendations and, if used, the risk of suicide should be assessed and monitored particularly closely.”  However a retrospective cohort study published in Pediatrics, in January 2014 found “no evidence that risk of suicide attempts differed for commonly prescribed SSRI and SNRI antidepressants” in a comparison of “medically treated suicide attempts among new users of sertraline, paroxetine, citalopram, escitalopram, and venlafaxine to risk for new users of fluoxetine.” 

Clearly, the questions of suicidality, risk for completed suicides, and the balance of morbity and mortality from depression left untreated by SSRI will continue to be investigated. In the meantime, to aid the practicing physician, the AAP has published guidelines in 2013 which state that when managing an adolescent with depression, they “should receive evidence-based interventions, including CBT, IPT, or SSRIs, delivered in any clinical setting where such capability exists.” They specifically mention fluoxetine as a defensible choice. A current reading of the scientific and professional literature thus supports the conscientious use of pharmacological treatment of depression in certain pediatric patients, though the balance of evidence can be expected to evolve, perhaps eventually supporting a wider formulary than is currently employed by the most conservative pediatricians managing these patients.

Types of antidepressants used in children and adolescents include:

Suicidality and Balancing the Risks

At the heart of the controversy lies the question of whether SSRI treatment increases suicidality or suicidal attempts/completions in pediatric patients. Of course, depression in and of itself is relatively strong risk factor for these behaviors and thought patterns. Measuring and balancing these risks sits at the heart of the role of pediatric SSRI use. While the AAP recommendations discussed above advocate for the use of antidepressants in adolescent populations, the FDA black-box warning still stands. As such, responsible clinicians ought to manage and continually assess the suicide risk in their depressed patients, whether pharmacologically treated or not. Several validated tools for screening exist, with the Columbia-Suicide Severity Rating Scale having a pediatric-specific set of questionnaires.

Interestingly, there is some evidence that reluctance to prescribe SSRIs is correlated with an increase in suicidality in children and adolescents. Quoting Gibbons, et al, “SSRI prescriptions for youths decreased by approximately 22% in both the United States and the Netherlands after the warnings were issued. In the Netherlands, the youth suicide rate increased by 49% between 2003 and 2005 and shows a significant inverse association with SSRI prescriptions. In the United States, youth suicide rates increased by 14% between 2003 and 2004, which is the largest year-to-year change in suicide rates in this population since the Centers for Disease Control and Prevention began systematically collecting suicide data in 1979.”

In conclusion, there are unsettled questions, but one would be operating within the professional norm when prescribing fluoxetine to depressed pediatric patients. More importantly, coupled with good screening techniques and patient relationships, there is evidence that such practice may well reduce morbidity and mortality from major depression in children and teenagers.

Patient Resources

The following websites may be useful for patients and their families. 

https://foundrybc.ca/

https://keltymentalhealth.ca/collection/antidepressantanti-anxiety-medications

References:

1. Gibbons et al. Early evidence on the effects of regulators suicidality warnings on SSRI prescriptions and suicide in children and adolescents. American Journal of Psychiatry. Sept 2007; 164: 1356-1363.
2. Olfson et al. Relationship between antidepressant medication treatment and suicide in adolescents. Archives of General Psychiatry. Oct 2003; 60(10): 978-982.
3. Gibbons et al. The relationship between antidepressant prescription rates and rate of early adolescent suicide. American Journal of Psychiatry. Nov 2006; 163 (11): 1898-1904.
4. Hamad et al. Suicidality in pediatric patients treated with antidepressant drugs. Archives of General Psychiatry. March 2006; 63: 332-339.
5. Hetrick et al. Selective serotonin reuptake inhibitors for depressive disorders in children and adolescents. Cochrane Database of Systematic Reviews. 2008:1.
6. Katz L et al. Effect of Regulatory warnings on antidepressant prescription rates, use of health services, and outcomes among children, adolescents, and young adults.  CMAAJ. 2008 April 8;178(8) 1005-11

7. Dwyer, J. B. & Bloch, M. H. Antidepressants for Pediatric Patients. Curr Psychiatr 18, 26–42F (2019).

8. Kennard, B. D. et al. Remission and Recovery in the Treatment for Adolescents with Depression Study (TADS): Acute and Long-term Outcomes. J Am Acad Child Adolesc Psychiatry 48, 186–195 (2009).