High-Dose Antidepressants in Youth May Up Risk for Self-Harm

Pam Harrison

April 28, 2014

Children and young adults who are started on higher doses of antidepressants than are typically prescribed are at least twice as likely to engage in acts of deliberate self-harm (DSH), new research suggests.

Matthew Miller, MD, and colleagues from the Harvard School of Public Health, Boston, Massachusetts, and from the University of North Carolina, Chapel Hill, found that the rate of DSH among children and adults 24 years of age or younger who were prescribed high-dose antidepressant therapy was approximately twice as high as that seen among matched control individuals who were prescribed "modal-dose" therapy, with a hazard ratio (HR) of 2.2.

This corresponds to approximately 1 additional DSH event for every 150 patients treated with high-dose rather than modal-dose therapy, as the authors point out.

In contrast, the absolute risk for suicidal behavior was far lower among adults between 25 and 64 years of age, and the difference between those who received high-dose antidepressant therapy and those who received modal-dose therapy was effectively 0.

"This is the first prospective cohort study to examine the relation between dose of antidepressants and the risk of DSH," Dr. Miller told Medscape Medical News. "And the clinical implications of our findings indicate that physicians should avoid initiating pharmacotherapy at high therapeutic doses and to monitor all patients starting antidepressants, especially youth, for several months and regardless of history of DSH."

The study was published online April 28 in JAMA Internal Medicine.

Comprehensive Meta-analysis

A comprehensive meta-analysis of randomized trial data had previously suggested that suicidal behavior is twice as likely when children and young adults are randomly assigned to antidepressant therapy compared with placebo control participants.

However, according to the same meta-analysis, drug-related risk was not elevated for adults 24 years of age and older.

The current study was a propensity score-matched cohort study done using population-based healthcare utilization data from 162,625 residents between 10 and 64 years of age with depression.

All patients had received a selective serotonin reuptake inhibitor (SSRI), given at either a modal dose or a higher-than-modal dose between January 1, 1998, and December 31, 2010.

Modal doses for citalopram, sertraline (Zoloft, Pfizer Inc), and fluoxetine were 20 mg/day, 50 mg/day, and 20 mg/day, respectively.

Dr. Miller pointed out that high doses of the same SSRIs were defined as any dose higher than the modal dose, but they were still within the therapeutic range.

Analyses were restricted to new initiators of antidepressant therapy rather than prevalent users, because this allowed researchers to detect adverse events that follow soon after treatment initiation and to control for selection bias.

The age and sex distributions among high-dose vs modal-dose initiators were almost identical. The distribution of their constructed tiers of depression severity also differed little across dose categories.

Table. Rate of DSH per 1000 Person-Years by Dose and Age Group

Dose Patients Initiating Rx (No.) DSH Events DSH Rate (per 1000 Person-Years)
Age 10-24 years      
High 7116 74 31.5
Modal 14,189 68 14.7
Age 24-64 years      
High 23,637 32 3.2
Modal 45,002 49 2.8


Mechanism Not Clear

"In our primary analysis of the 10- to 24-year-old cohort, for every 1000 patients initiating high-dose therapy there were approximately 7 (7.3) more DSH events over the first 90 days of treatment among high-dose initiators compared with modal dose initiators," the authors write. "The corresponding number needed to harm was 136."

No effect on DSH behavior was seen between the 2 dosing groups for participants older than 24 years. Asked why he thought the increased risk for DSH was seen only in children and young adults and not in older adults, Dr. Miller said that the same pattern has been seen in randomized controlled trials (RCTs) of antidepressants vs placebo.

"The reasons are not clear," he added, "[but] to the extent to which depression-independent suicidogenic effects of antidepressants exist, older adults may be less susceptible, on balance, if antidepressive efficacy is superior for older adults compared with children and younger adults."

Dr. Miller also suggested that the higher dose-related suicide risk among children and young adults might also reflect an age-related susceptibility to suicidogenic effects of antidepressants that is independent of depression severity.

He noted that this too has been observed in RCTs with placebo controls.

Then again, the elevated risk for DSH among young persons receiving higher-dose therapy might also be due to more frequent and severe drug discontinuation syndromes among this group of patients compared with modal-dose recipients.

However, Dr. Miller felt that withdrawal reactions were unlikely to play a major role in the increased risk for DSH among high-dose recipients.

Approximately half of all patients in whom high-dose antidepressant therapy was initiated had prescriptions written by internists or general practitioners, the authors note.

"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," they conclude.

Start Low, Go Slow

In an accompanying editorial, David Brent, MD, University of Pittsburgh, and Robert Gibbons, PhD, University of Chicago, ask an obvious question: why were 18% of patients in this analysis treated with high initial doses of antidepressants, especially inasmuch as this practice goes against current clinical guidelines?

The recommended practice is to initiate antidepressant treatment at the equivalent of 10 mg/day of fluoxetine for 1 week and then increase the dosage to 20 mg/day for the next 3 weeks.

Only after that treatment interval should physicians consider dose escalation if patients are not responding adequately to treatment.

"The decision to initiate treatment at a higher dose...suggests there was something different about these patients that may have also put them at greater risk for DSH, such as a history of treatment nonresponse or a history of a positive response only at a higher than modal dose," the editorialists speculate.

They also speculate that it is possible that those patients who were started on higher doses of an SSRI experienced more adverse effects, which caused them to discontinue the drug, and that it was the discontinuation of the drug rather than the higher dose per se that increased the risk for DSH.

"In summary, Miller et al are to be commended on a thoughtful and careful analysis of the effects of initiating antidepressants at higher than modal dosages," the editorialists write.

"Their findings...add further support to current clinical recommendations to begin treatment with lower antidepressant doses," although the editorialists note that individual differences in drug metabolism could necessitate a higher dose in some patients in order to achieve adequate blood levels and subsequent therapeutic response.

Dr. Miller received support for the study from the National Institute of Mental Health. Dr. Brent receives royalties from Guilford Press, among other sources. Dr. Gibbons is president and founder of Psychiatric Assessments Inc, a corporation that uses the trade name Adaptive Testing Technologies, through which Computerized Adaptive Test–Mental Health will be made commercially available.

JAMA Int Med. Published online April 28, 2014. Abstract, Editorial


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