Suicide doubles in young patients starting high-dose SSRIs

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Why start at high modal doses?

One obvious question raised by this thoughtful and careful study is: Why were so many patients – approximately 18% – treated with high initial doses of SSRIs, contrary to clinical guidelines?

Modal starting daily doses are 20 mg for citalopram, 50 mg for sertraline, and 20 mg for fluoxetine. The decision to initiate treatment at higher doses than these "suggests there was something different about these patients that may have also put them at greater risk for [deliberate self-harm]," such as a history of treatment nonresponse or a history of a positive response only at high doses, said Dr. David A. Brent and Robert Gibbons, Ph.D.

"It is also possible that patients started on higher doses experienced more adverse effects, discontinued the medication, and that it was the discontinuation rather than the higher dose per se that put the patient at increased risk" for suicide, they noted.

Dr. Brent is in the departments of medicine and health sciences, as well as at Western Psychiatric Institute and Clinic, at the University of Pittsburgh. Dr. Gibbons is at the University of Chicago. Dr. Gibbons has been an expert witness for Pfizer Pharmaceuticals in cases related to suicide and adverse neuropsychiatric events for the drugs neurontin and varenicline; no other potential financial conflicts of interest were reported. These remarks were taken from Dr. Brent’s and Dr. Gibbons’s invited commentary accompanying Dr. Miller’s report (JAMA Intern. Med. 2014 April 28 [doi:10.1001;jamainternmed.2013.14016).



Children, adolescents, and young adults with depression who begin taking SSRIs at "higher than modal" doses appear to be at twice the risk for suicide as patients aged 25 years and older who do so, according to a report published online April 28 in JAMA Internal Medicine.

In what they described as "the first prospective cohort study to examine the relation between dose of antidepressants and the risk of deliberate self-harm," investigators assessed nationally representative data from health care plans for 162,625 patients aged 10-64 years who were diagnosed as having depression and initiated citalopram, sertraline, or fluoxetine therapy during a 12-year period. These patients were categorized by whether they started on the most commonly prescribed (modal) doses of these agents or on higher than modal doses that still were not in excess of the recommended maximum dose, said Dr. Matthew Miller of the department of health policy and management, Harvard School of Public Health, Boston, and his associates.

These two study groups were well balanced for sex, depression severity, and suicidal ideation at baseline. In the 10- to 24-year-old age range, 142 patients attempted suicide within 1 year; the rate was 14.7 suicide events per 1,000 person-years in those who started selective serotonin reuptake inhibitors (SSRIs) at modal doses, but more than twice as high – 31.5 suicide events per 1,000 person-years – in those who started at high modal doses. In comparison, among older adults these rates were only 2.8 per 1,000 person-years in those who started SSRIs at modal doses and 3.2 per 1,000 person-years in those who started at high modal doses, the investigators reported (JAMA Intern. Med. 2014 April 28 [doi:10.1001/jamainternmed.2014.1053]).

"In our primary analysis of the 10- to 24-year-old cohort, for every 1,000 patients initiating high-dose therapy, there were approximately seven more [suicide] events over the first 90 days of treatment ... compared with modal-dose initiators. The corresponding number needed to harm was 136. For the older cohort, the risk difference was essentially zero," Dr. Miller and his associates wrote.

In effect, "we expect approximately one additional [suicide] event for every 136 patients 10-24 years of age who are treated with high-dose therapy instead of modal-dose therapy," they noted.

"Considered in light of recent meta-analyses concluding that the efficacy of antidepressant therapy for youth seems to be modest, and separate evidence that dose is generally unrelated to the therapeutic efficacy of antidepressants, our findings offer clinicians an additional incentive to avoid initiating pharmacotherapy at high therapeutic doses and to monitor all patients starting antidepressants, especially youth, for several months and regardless of history of deliberate self-harm," Dr. Miller and his colleagues said.

Another notable finding in this study was that for nearly half of all patients who initiated SSRI therapy at high modal doses, the prescriptions were written by internists or general physicians. Among patients aged 24 years and younger, internists/general physicians wrote about one-third of high modal-dose prescriptions, pediatricians wrote 10%, and psychiatrists/psychologists wrote 30%. This "underscores the relevance of our findings to clinicians caring for patients in both specialty and nonspecialty settings," they added.

The investigators cited several limitations. For example, their analysis is based on administrative data, which means that antidepressant adherence was not measured directly.

This study was supported in part by the National Institute of Mental Health, the National institute on Aging, and the Agency for Healthcare Research and Quality. Dr. Miller reported no financial conflicts of interest; one of his associates was supported in part by GlaxoSmithKline, Merck, and Sanofi.

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