Fluoxetine in children

Emslie, G.J., Rush, A.J., Weinberg, W.A., Kowatch, R.A., Hughes, C.W., Carmody, T., and Rintelmann, J.A. (1997) double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 54 1031-1037. 

Riddle, M.A., King, R.A., Hardin, M.T., and Scahill, L. (1991) Behavioral side effects of fluoxetine in children and adolescents. / Child Adolesc Psychopharmacol 1 ... 

A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Archives of General Psychiatry, 54, 1031-1037. 

Jain, J., Birmaher, B., Garcia, M., Al-Shabbout, M., c Ryan, N. (1992). Fluoxetine in children and adolescents with mood disorders A chart review of efficacy and adverse reactions. Journal of Child and Adolescent Psychopharmacology, 2, 259—265. 

Although favorable reports for other SSRIs have been reported in open-label studies (reviewed by Posey et al., 2006), these are of doubtful value for the reasons discussed above. The fact that the largest, most comprehensive study to date failed to find a benefit of a SSRI for the specific indication for which these agents are most commonly prescribed in ASD casts doubt on the value of this class of medications in ASD. Indeed, aside from one study of fluvoxamine in adults (McDougle et al., 1996) and one of fluoxetine in children (Hollander et al., 2005) (discussed above), there is little to support the use of SSRIs in ASD. Moreover, even in the studies that have reported favorable results, improvement in core symptoms has been found to be variable and generally rather modest, providing little support for the hypothesis that abnormalities in serotonin systems play a central role in autism. 

Emslie GJ, Rush AJ, Weinberg WA et al. A double-blind, randomized, placebo-controUed trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997 54 1031-7 Hazell P, O Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents. (Cochrane Review). In The Cochrane Library, Issue 1,2004. 

Data supporting efficacy of antidepressants in children and adolescents are sparse. Fluoxetine is the only antidepressant that is FDA approved for treatment of depression in patients less than 18 years of age. 

Suicidality in children and adolescents Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of olanzapine/fluoxetine or any other antidepressant in a child or adolescent must balance this risk with clinical need. 

Fluoxetine s most notable side effect is nervousness (>10% in adults) (Preskorn, 2000), which may be more common in the pediatric population (Teicher and Baldessarini, 1987). Fluvoxamine is less stimulating than fluoxetine but is a significant inhibitor of CYP3A4, which metabolizes common pediatric medications (Michalets and Williams, 2000). Fluvoxamine is most likely to cause constipation in adults (>10%) (Preskorn, 2000). This is an important consideration in children, given the often comorbid symptoms of en-copresis from overflow constipation. 

Mania. Mania and hypomania can also occur in children and adolescents on SSRIs, and, again, it is not known if there is an added developmental risk (Ven-kataraman et al., 1992). In a fluoxetine treatment study for depression, 3 (of 48) patients developed manic symptoms, even after excluding patients with psychotic depression, bipolar symptoms, or a family history of bipolar disorder (Emslie et al., 1997). In a paroxetine treatment study for depression, 5 adolescents (of 93) were removed for emotional lability and 1 for eupho-ria/expansive mood (Keller et al., 2001). 

Lethal overdosages are extremely rare (Barbey and Roose, 1998), but have been reported for fluoxetine (260 to 6000 mg), sertraline (1100 mg), paroxetine (530 to 600 mg), and fluvoxamine (unknown dose). Many of these lethal doses occurred in adults reports of lethal overdose in children occur even less frequently. One report of a 4-year-old boy who ingested 400 mg of fluvoxamine described life-threatening complications requiring respiratory and inotropic support (Fraser and South, 1999). The boy presented in a coma with hypotension and bradycardia. After 24 hours, he recovered. 

Kurlan, R., Como, P.G., Deeley, C., McDermott, M., McDermott, M.P. (1993) A pilot controlled study of fluoxetine for obsessive-compulsive symptoms in children with Tourette s syndrome. Clin Neuropharmacol 16 167-172. 

Emslie, G.J., Heiligenstein, J.H., Hoog, S.L., Judge, R., Brown E.B., and Nilsson, M. (2000) Fluoxetine for acute treatment of depression in children and adolescents a placebo controlled randomized clinical trial. Presented at the 39th Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico. 

Geller, D., Biederman, J., Reed, E., Spencer, T, and Wilens, T. (1995) Similarities in response to fluoxetine in the treatment of children and adolescents with obsessive-compulsive disorder. / Am Acad Child Adolesc Psychiatry 34 36—44. 

Sovner et al. (1998) have done an excellent job summarizing the data on antidepressants in patients with developmental disabilities. There have been nine reports of antidepressant use in adults with depression and MR and three reports of antidepressant use in children and adolescents. Eight of nine reports in adults were positive. The drugs studied included nialimide (n = 27), fluoxetine (9), imipramine (6), amoxapine (2), and nortriptyline (1) (total n = 45). In addition, Sovner et al. identified four reports of antidepressant use in children. One involved successful treatment with fluoxetine in an adolescent, another indicated efficacy with imipramine and amitriptyline in 9 of 12 children (Do-sen, 1982), and a third showed successful management in 3 of 4 children treated with imipramine or tryptophan plus nicotinamide (Dosen, 1990). One study of fluoxetine in depressed children with autism and MR witnessed improvement in depression but not in compulsive symptoms (Ghaziuddin and Tsai, 1991). 

Fairbanks, J., Pine, D.S., Tancer, N.K., Dummit, E.S., Kentgen, L.M., Martin, J., Asche, B.K., and Klein, R.G. (1997) Open fluoxetine treatment of mixed anxiety disorders in children and adolescents. J Child Adolesc Psychopharmacol 17 17—29. 

In four instances, the agency has invoked this rule at the time of approval of supplements for new indications for psychotropic drugs already approved for other psychiatric indications. It was noted in the approval letters for these supplements that, since the drugs in question would likely be used in children and/ or adolescents with the newly approved indications, the FDA required the sponsors of these products to conduct studies that would be pertinent to such use in the pediatric population. Since the products were ready for approval in adults, the FDA deferred the required pediatric studies to a future date. Alternatively, sponsors could make an argument for waiver of the requirement. The drug products and indications for which the FDA has required studies under the Pediatric Rule are as follows paroxetine for social anxiety disorder sertraline for post-traumatic stress disorder (PTSD) olanzapine for acute mania in bipolar disorder and fluoxetine in premenstrual dysphoric disorder (PMDD). 

Finally, a small, double-blind, placebo-controlled, crossover trial of fluoxetine in 14 children and adolescents with OCD also showed a significant decrease in CY-BOCS total scores (151). 

Few trials have tested the potential efficacy of SSRIs to treat anxiety disorders other than OCD in children and adolescents. Black and colleagues ( 162) found a significant difference between fluoxetine and placebo in four of six children with selective mutism (believed to be a variant of social phobia) but only on the global rating of change and parent s rating of mutism change. In another small open-trial study, fluoxetine (10 to 60 mg per day) reduced anxiety and increased speech in 76% of children (age 5 to 14 years) with selective mutism (163). 

In Great Britain, all SSRI antidepressants, except fluoxetine, have been banned for use in treating depression in children. The main concern surrounded suicidality that was increased with SSRIs in general, including fluoxetine (Committee on Safety of Medicines, 2003). 

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