Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents
Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, et al.;
Commented by , 31 Aug 2007
Aim of the study
Have regulatory warnings regarding the risk of suicide in children and adolescents with selective serotonin re-uptake inhibitor (SSRI) use (i) reduced the rate of prescription of these medications, and if so (ii) is this associated with an increase in suicide rates in this group?
Method
In the United States, SSRI prescription rates were estimated from the IMS Health Database of pharmacies, and suicide rates were calculated from data from the Centre of Disease Control and Prevention (CDC) WONDER Compressed Mortality database (1998 – 2002) and CDC WISQARS Injury Mortality Report (2003-2004).
In the Netherlands, SSRI prescription data was estimated from, the PHARMO database (representing 12% of the Dutch population) and suicide data was collected from the Central Bureau of Statistics (1998 – 2005).
Results
The warnings were issued in 2003-2004. In the United States in 2004, prescription of SSRIs decreased in all age groups except for those over 60, where it increased at a rate similar to that seen prior to the warnings. Suicide rates in 5-19 year olds increased 14% from 2003 to 2004. In contrast, the number of suicides continued to decrease in the over 60s.
In the Netherlands, the SSRI prescription pattern pre and post warnings were comparable to that seen in the US. A significant, inverse relationship between suicide rates in children and adolescents and SSRI prescription rates was found for the 1998-2005 time period (p<0.04).
Dr Hood's and Prof Nutt's comments
The initial FDA warnings about the dangers of SSRIs in youth were based upon data from some randomised controlled trials which found suicidal ideation and behaviour increased in adolescents prescribed these antidepressants (ref. 1). Most ecological studies, such as that reported here, have failed to support this finding, and often find evidence that is more consistent with the suggestion the antidepressant treatment is protective against suicide (ref. 2, ref. 3, ref. 4, ref. 5). In addition it has been suggested that this finding might be an artefact of data collection as it has since been seen in a trial of psychotherapy (ref. 6).
Although the Gibbons et al. study cannot demonstrate causation, it does provide preliminary evidence that the FDA warning had the potential to harm. As these authors pointed out, prescriptions for non-serotonergic specific antidepressants and tricyclic antidepressants have also reduced for the under 20s, and there is little evidence that alternative treatment such as psychotherapy are being utilised, perhaps because they are both ineffective (ref. 7) and may cause harm (ref. 8).
Somewhat alarmingly, the diagnosis of major depression in the paediatric population by paediatricians and primary care physicians also declined over this period – and although treatment by psychiatrists increased a little after the FDA advisory this was not enough to compensate for the decline observed by other practitioners (ref. 8).
A parsimonious explanation is that the FDA warning prompted our non-psychiatrist colleagues to back away from diagnosing and treating this cohort, transferring some of this burden to psychiatrists and leaving the remainder without effective treatment.
Although much of the focus has been on the use of these medications as antidepressant agents, SSRIs are increasingly used as (off-licence) treatments of anxiety disorders in youth, where they are effective (ref. 9). Additionally, it is now evident that adolescent anxiety disorders – if untreated – often progress to major depressive disorder (ref. 10, ref. 11).
Thus, another consequence of the drop in SSRI prescriptions in this group may be increased anxiety morbidity and, in turn, later development of depression and potentially suicidal ideation.
This news of decreased SSRI use in youth may be a cause for celebration for those who fear that psychiatrists overdiagnose and overmedicate, however we recommend leaving the champagne on ice a little longer. Articles such as this by Gibbons et al. are a sobering reminder that regulatory decisions are not to be taken lightly, may have perverse outcomes, and that even a decision not to prescribe may have unintended adverse consequences.
References
1. Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, et al. ACNP Task Force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology 2006; 31 (3); 473-492
2. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant prescription rates and rate of early adolescent suicide. American Journal of Psychiatry 2006; 163 (11); 1898-1904
3. Isacsson G, Boëthius G, Bergman U. Low level of antidepressant prescription for people who later commit suicide: 15 years of experience from a population-based drug database in Sweden. Acta Psychiatrica Scandinavica 1992; 85 (6); 444-448
4. Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Archives of General Psychiatry 2003; 60 (10); 978-982
5. Valuck RJ, Libby AM, Sills MR, Giese AA, Allen RR. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs 2004; 18 (15); 1119-1132
6. Bridge JA, Barbe RP, Birmaher B, Kolko DJ, Brent DA. Emergent suicidality in a clinical psychotherapy trial for adolescent depression. American Journal of Psychiatry 2005; 162 (11); 2173-2175
7. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 2004; 292 (7); 807-820
8. Libby AM, Brent DA, Morrato EH, Orton HD, Allen R, Valuck RJ. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. American Journal of Psychiatry 2007; 164 (6); 884-891
9. Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007; 297 (15); 1683-1696
10. Bittner A, Goodwin RD, Wittchen HU, Beesdo K, Höfler M, Lieb R. What characteristics of primary anxiety disorders predict subsequent major depressive disorder? Journal of Clinical Psychiatry 2004; 65 (5); 618-626; quiz 730
11. Wittchen HU, Hoyer J, Friis R. Generalized anxiety disorder - a risk factor for depression? International Journal of Methods in Psychiatric Research 2006; 10 (1); 52-57