The overall relationship between antidepressant medication prescription and suicide rate was not significant, according to a study conducted by J. John Mann, MD, and colleagues—the latest entry in the ongoing debate concerning the safety of antidepressants. The researchers found that prescriptions for selective serotonin reuptake inhibitors (SSRIs) and other new-generation non-SSRI antidepressants were associated with lower rates of suicide. However, the investigators did find a positive association between tricyclic antidepressants (TCAs) and suicide rate.

Dr. Mann’s study, appearing in the February Archives of General Psychiatry, was published at about the same time that the FDA revised its requested black box warning labeling from last fall. The agency now officially advises that the labels of all antidepressant medications state that antidepressants increased the risk of suicidal thinking and behavior in children and adolescents in short-term studies, as opposed to having a causal role in inducing suicidality.

The results from Dr. Mann’s study were adjusted for age, sex, race, income, and county-to-county variability in suicide rates. Higher suicide rates in rural areas were associated with fewer antidepressant prescriptions, lower income, and relatively more prescriptions for TCAs.

“The aggregate nature of these observational data preclude a direct causal interpretation of the results,” the researchers reported. “A high number of TCA prescriptions may be a marker for those counties with more limited access to quality mental health care and inadequate treatment and detection of depression, which in turn lead to increased suicide rates. By contrast, increases in prescriptions for SSRIs and other new-generation non-SSRIs are associated with lower suicide rates both between and within counties over time and may reflect antidepressant efficacy, compliance, a better quality of mental health care, and low toxicity in the event of a suicide attempt by overdose.”

Regarding the physician’s role in helping a patient with depression, “Treatment is better than no treatment,” Dr. Mann said, but clinicians should “monitor response and side effects carefully and adjust dose accordingly.” As for the FDA’s softened warning, “The data are not there to determine a causal role,” he commented. “The safety record [of antidepressants] in adults is very good,” he continued. “The studies in kids were too small and lacked a reference compound in all but one study, so no firm conclusions can be drawn beyond the need to monitor carefully.” Dr. Mann is a Professor of Psychiatry and Radiology at Columbia University and Chief of the Neuroscience Department at New York Psychiatric Institute, New York City.

A NATIONAL COUNTY-LEVEL STUDY

Dr. Mann and colleagues examined the relationship between antidepressant medication prescription and suicide rate by analyzing associations at the county level across the United States. Their study incorporated National Vital Statistics from the CDC from all US counties. Information for each US resident who committed suicide between 1996 and 1998 was included in the database. The primary outcome measure was the suicide rate in each county expressed as the number of suicides for a given population size.

The study’s findings persisted following the adjustment for median county income, “suggesting that a high relative prescription rate of TCAs is not simply an indicator of limited access to quality mental health care but that choice of treatment matters. In that regard, it is notable that more TCA prescriptions are associated with fewer overall antidepressant prescriptions and lower income.”

Dr. Mann believes that the increase in non-TCA prescriptions in the US is most likely associated with treatment of more patients for depression and can thereby potentially lower suicide rates insofar as suicide most commonly occurs in patients with untreated depression. “The effect is limited because the highest-risk group may have a lower rate of antidepressant prescriptions and poorer compliance than the rest of the patient population with depression,” he reported. “The low base rate of suicide and the exclusion of suicidal patients from antidepressant treatment trials likely explain why randomized, controlled, antidepressant medication trials have failed to show a reduction in suicide rates. In contrast, studies with a priori aims of studying antisuicidal effects of medications in at-risk individuals can show efficacy. For example, clozapine has a superior antisuicidal effect compared with olanzapine in suicidal patients with schizophrenia, and lithium carbonate has antisuicidal superiority in mood disorders.”

STUDY LIMITATIONS

Dr. Mann acknowledged limitations to his study, including the fact that medication estimates were based on outpatient use. In addition, some uncontrolled variability in the suicide rate data occurred due to regional differences in definition of suicide, qualifications of the coroner or medical examiner, the extent to which cases are investigated, the relationship between prescription rates and taking of medication (which may be weaker in high-risk groups), and the quality of preparation of official statistics (which can lead to differential underreporting of suicide rates). “Despite this potential variability, strong associations between antidepressant prescription rates and suicide rates were observed,” he stated. “Furthermore, since the associations were in opposite directions for TCAs versus SSRIs and newer non-SSRIs, this variability is not producing systematic bias.”

One possible explanation for the higher mortality due to suicide by persons taking TCAs relative to SSRIs is that TCAs are more toxic in overdose; thus death rates due to TCA overdose are higher relative to prescription volume, compared with SSRIs and other new-generation antidepressants, Dr. Mann offered. “Given earlier concerns about the safety of SSRIs in adults with depression in terms of suicide risk and more recent concerns about the safety of SSRIs in youth with depression, our results and those of Olfson et al, who performed a similar but less sophisticated analysis in youth, indicate that more SSRI prescriptions are associated with fewer suicides in adults and youth,” he said. “The risk-benefit ratio associated with prescription of these antidepressants must be clearly favorable to explain the relationships observed in our study.”

RESEARCH AND POLITICS

Last September, Dr. Mann testified at the second FDA public hearing on the topic. As President of the American Foundation for Suicide Prevention, he urged federal advisers to consider all aspects of treatment with antidepressants and emphasized that untreated depression, as opposed to use of antidepressant medication, was a greater threat to life. “When you do psychological autopsies and talk to the families who have lost their loved ones, it is clear that the principal problem in these suicides is not that they have been taking antidepressants,” Dr. Mann told the committee. “The principal problem is that most have taken no antidepressants, and a small minority have taken low doses of antidepressants, and very few have had adequate treatment. Those areas of the US that have the highest prescription rates of SSRIs, both in adults and children, have had the biggest falls in suicide rates.”

Dr. Mann has also cochaired the American College of Neuropsychopharmacology, which last year made public similar findings on SSRIs. Several years ago, he was an expert witness for GlaxoSmithKline in a civil trial. He was deposed once, but never appeared in a trial for Pfizer Inc, “because I believe the use of SSRIs for depressed patients who need treatment would be reduced if people incorrectly believed the drug caused individuals to commit homicide or suicide.” In addition, in the last 15 years, he has had two studies funded by drug companies, both of which “had nothing to do with testing efficacy of any medication,” he said, and accounted for less than 1% of his research grant support.

OTHER OPINIONS ON SSRIs

A trio of studies appeared in the February 19 BMJ concerning the use of SSRIs. Fergusson and colleagues reviewed data from more than 87,000 patients and found a significant increase in the odds of suicide attempts for patients receiving SSRIs compared with those taking a placebo. They also noted an increase in the odds ratio of suicide attempts in comparing SSRIs with therapeutic interventions other than TCAs. In a pooled analysis of SSRIs versus TCAs, they did not observe a difference in the odds ratio of suicide attempts.

In another report, Gunnell and colleagues found no evidence that SSRIs increased the risk of suicide, but they also noted that an increased risk of suicide and self-harm caused by SSRIs could not be ruled out. Furthermore, Martinez et al found no evidence that the risk of suicide or nonfatal self-harm in adults who were prescribed SSRIs was greater than in those prescribed TCAs. They did find weak evidence of an increased risk of nonfatal self-harm for current SSRI use among those 18 or younger.

—Colby Stong

Suggested Reading
Fergusson D, Doucette S, Glass KC, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ. 2005;330:396-402.
Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry. 2005;62:165-172.
Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA’s safety review. BMJ. 2005;330:385-389.
Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ. 2005;330;389-395.
Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry. 2003;60:978-982.

Return to table of contents