The Relationship Between Antidepressant Initiation and Suicide Risk
Psychiatric Times, December 31, 2014
By Robert D. Gibbons, PhD and J. John Mann, MD
http://www.psychiatrictimes.com/special-reports/relationship-between-antidepressant-in
itiation-and-suicide-risk#sthash.Liim80Gy.dpuf(Article text is below the Figures)

Figure 1. Suicide rate multipliers for SSRIs, SNRIs, and TCAs relative...

Figure 2. Suicide rate vs SSRI dose in Japan stratified by age

Figure 3. Nonproportional hazards model for suicide attempts over timeFigure 4. Probabilities of suicide risk in adult and geriatric fluoxet...
There has been much debate about whether certain classes of medications (eg,antidepressants) increase the risk of suicidal behavior and whether that risk is greaterin children, adolescents, and young adults. In 2004, the FDA placed a black box
warning on all antidepressants because of concerns that the medications increase riskof suicidal thoughts and behavior in youths; in 2006, the warning was extended toinclude young adults (up to age 26). The FDA based its black box warning on results of
its meta-analyses of randomized controlled trials (RCTs) conducted in pediatric andadult psychiatric and nonpsychiatric populations.
History
Questions regarding a possible relationship between antidepressants and suicide werefirst raised in 1990 with the publication of a series of case reports in which the thennewly introduced SSRIs were associated with the apparent emergence of suicidal
thoughts and behavior.1 This led to FDA hearings in 1991, but no evidence of anincreased risk of suicidal acts associated with antidepressants was found. In October
2004, concerns raised over paroxetine use in children and adolescents eventually ledthe FDA to issue a black box warning regarding antidepressants and suicide forchildren younger than 18 years.
The evidence supporting the first black box warning came from a meta-analysis thatcombined spontaneous reports of suicidal thoughts and behaviors from pediatric
RCTs of newer antidepressants, mostly SSRIs.2 The risk of suicidal ideation andbehavior, or suicidality, was found to be higher for children treated withantidepressants than for those given placebo (odds ratio [OR] = 1.78; 95% confidence
interval [CI], 1.14, 2.77). The FDA also presented results of an analysis of prospective
data (suicidal ideation or behavior rating-scale item) that showed no effect for
emergence (OR: 0.93; 95% CI: 0.75, 1.15) or emergence and/or worsening of suicidal
thoughts and behavior in the active-drug group compared with the placebo group (OR= 0.92; 95% CI, 0.76, 1.11).
The inconsistency between the prospective clinician ratings and spontaneous patientreports has not been adequately explained. It may be due to bias because patientsrandomized to active drug treatment have a greater likelihood of adverse effects ingeneral, leading to more contact or conversation with study staff and increased
chance of having any suicidal thoughts observed. Similarly, overdose on study
medication is more likely to be reported if it results in the need for medical attention,
as would be true for patients who receive active treatment rather than placebo.
Systematic questioning in a setting such as the emergency department or inpatient
service generally gives a more accurate rate of suicidal ideation and behavior than dospontaneous reports. The FDA based its decision on the “signal” of risk fromspontaneous adverse-event reports and not on the absence of a signal of risk fromsystematic clinician evaluations.
In January 2006, the FDA conducted a second meta-analysis of 372 RCTs of newer
antidepressants in an adult population of approximately 100,000 patients.3 This
analysis was based on spontaneous adverse-event reports from the RCTs and did notprovide data from prospective clinician ratings. Overall, the analysis revealed noevidence of more suicide-related adverse reports in the antidepressant group than in
the placebo group. Stratification by age showed that for the primary endpoint ofsuicidal ideation or behavior, for 18- to 24-year-olds, the risk was increased withmedication compared with placebo, and the risk approached significance (OR = 1.62;
95% CI, 0.97, 2.71); for adults aged 25 to 64 years, the risk was significantly decreased

(OR = 0.79; 95% CI, 0.64, 0.98); and for geriatric patients, the risk was markedly
decreased (OR = 0.37; 95% CI, 0.18, 0.76) with antidepressants relative to placebo. On
the basis of these results, the FDA extended the black box warning to cover 18- to
24-year-olds.
More recent data
Since the FDA warnings, studies have been conducted to explore the relationshipbetween initiation of antidepressant treatment and suicidal events. We review several
lines of evidence that range from the weakest data based on spontaneous reports tothe most rigorous data based on RCTs.

Spontaneous reports. Spontaneous reports to the FDA can be made by anyone; mostare from patients, physicians, pharmaceutical companies, and plaintiff attorneys. They
report both an adverse event and a listing of one or more medications that a patient istaking at the time of the event. Use of the spontaneous reporting systems for drug
safety determination is highly problematic. Some limitations regarding these data are:• Confounding by indication (ie, patients taking a particular drug may have a disease
that is itself associated with a higher incidence of the adverse event)• Systematic underreporting• Effects of publicity in the media on numbers of reports• Duplication of reports• Attribution of the event to a single drug when patients may be taking multiple drugs• Missing data
These limitations degrade the capacity for optimal data mining and analysis, and any
conclusions must be tentative and require validation by another data source.4
Data from the FDA Adverse Event Reporting System (MedWatch) from 1998 to 2004
for all antidepressants and completed suicide were analyzed by our group.5 The
dataset comprised a total of 28,317,382 records, including all reported adverse eventsand drug combinations. A national prescription rate for each antidepressant by year isthe denominator in the analysis. Figure 1 presents a plot of the estimated rate
multipliers and confidence limits for each drug. As a class, both SSRIs and SNRIs have

rate multipliers that are significantly less than 1.0 (ie, lower than the national averagesuicide adverse-event report rate for antidepressants as a class). By contrast, TCAs
have rate multipliers that are significantly above the national average suicide rate for
antidepressants. TCAs have a significantly higher risk of suicide adverse-event
reports than do SSRIs and SNRIs.
This is striking because one might anticipate an increase in reports related to SSRIs
given the highly publicized concern over a possible link between suicide and the use of
SSRIs. However, TCAs are much more toxic than SSRIs on overdose and are much
more likely to produce a medically serious outcome. Therefore, it may be important toseparate reports of medically serious overdoses using TCAs or SSRIs. Comparing theincidence of other types of suicide-related reports for these classes of medication
may clarify the situation.

Ecological studies. For very rare events, such as those that occur at rates of 1 in
10,000 or less (eg, death by suicide), there are few options for routine drug
surveillance because very large populations of patients are needed to detect enoughevents to be informative. One approach is to use ecological data that relate changes
in drug prescription rates to suicide rates in large populations.
Decreases in suicide rate over time have been shown to correlate with increased
antidepressant use in many studies around the world, including those in Europe,
Scandinavia, the US, and Australia. In Sweden, the doubling of prescriptions for SSRIs
correlated with a 25% decrease in the suicide incidence.6 In an analysis of 27 countries,
Ludwig and Marcotte7 showed that an increase of 1 pill per capita (a 13% increase over1999 levels) was associated with a 2.5% reduction in suicide rates, a relationship thatwas more pronounced in adults than in children.
Japan is a curious anomaly. Researchers there found a positive association between
suicide rates and antidepressant prescriptions.8Figure 2 clearly shows an overall
positive association between SSRI prescriptions and suicide rates; however,stratification by age reveals that within each age stratum, an inverse association isobserved. This is a classic illustration of Simpson’s paradox. What it indicates is thatin Japan, both suicide rates and use of antidepressants increase with age; however,for a given age-group, suicide rates have decreased with increasing SSRI
prescriptions over time.

Another anomaly is Iceland, where antidepressant prescription rates seemed
unrelated to lower suicide rates. Part of the reason for this are the traditionally
extremely low suicide rates in Iceland. This is a floor effect; there is so little room fora further decline in suicide rates that the relationship to prescription rates is
extremely hard to detect. Italy has had a decline in suicide rates linked toprescriptions for women but not for men. Most antidepressants in Italy are prescribed
for women, and so the ability to detect such a relationship is greater in women.
Ecological modeling from large numbers of small areas can also provide a stronger
basis for understanding the association between antidepressant medication use andsuicide completion. US county-level data on suicide rates and antidepressantprescription rates were analyzed for 1996 to 1998.9 After adjusting for sex, race, age,income, and unobservable county-level effects, the analyses revealed that increases
in SSRI and SNRI prescriptions were associated with decreases in suicide rates both
between and within counties over time. Conversely, counties with higher rates of TCA
prescriptions were associated with higher suicide rates; this may be because of thegreater toxicity of this class of agents and/or their more frequent use in areas withpoorer access to quality mental health services. This finding has been replicated inchildren and young adolescents (aged 5 to 14 years) and indicates that therelationship is robust and manifest across the life cycle, from childhood to adulthood.10

Large-scale observational studies. Valuck and colleagues11 examined the effects ofantidepressants on 24,119 adolescents with a first diagnosis of major depression. At
least 6 months of follow-up data were available, which showed that treatment with
SSRIs, other antidepressants, or combinations of antidepressants did not increase therisk of suicide attempts. Similar results were seen by Simon and colleagues.12,13
In contrast, Olfson and associates14 conducted a case-control study in depressedchildren and found a significant association for both suicide attempts (n = 263) andsuicide completion (n = 8) in children treated with antidepressants. Tiihonen andcolleagues15 found that current antidepressant use was associated with increased riskof suicide attempts but lower risk of suicide completion in youths who had beentreated with an antidepressant.
A cohort study of 226,866 veterans with newly diagnosed depression indicated thatthe attempted suicide rate was lower in those treated with only an SSRI
(monotherapy) than in those who did not receive an antidepressant (123/100,000 vs335/100,000, respectively; OR = 0.37; 95% CI, 0.29, 0.47).16 In SSRI-treated patients,
the rate of suicide attempts was lower after treatment (123/100,000) than before
treatment (221/100,000; relative risk = 0.56; 95% CI, 0.44, 0.71). Analyses stratified byage showed that the benefit for 18- to 24-year-olds was comparable to that for theolder age-groups: this contrasts with the FDA findings of greater risk in young adults
that prompted the extension of the black box warning to include this age-group.
These data have been reanalyzed using discrete-time survival analysis and showed arobust decrease in suicide attempt rate with SSRI monotherapy (hazard ratio = 0.17;
95% CI, 0.10, 0.28).17 As shown in Figure 3,
3 the incidence of attempted suicide
decreased concurrently with time from the index episode, and the hazard rate wasmuch lower for treated patients during the first few months following treatment
initiation; however, the difference becomes indistinguishable by 9 months following theindex episode. The lack of detectable benefit 9 months later may reflect a combinationof spontaneous remission of major depression in the placebo group and declining
compliance over time with treatment in the medicated group.

Randomized controlled trials. Bridge and colleagues18 analyzed an expanded set (27studies) of pediatric RCTs of antidepressant treatment and suicidality and found lesscorrelation between the two than the FDA’s original findings. Their report used alarger data set than the FDA’s and found a more favorable risk to benefit ratio.
In our research synthesis of longitudinal data, fluoxetine in youths, adults, and theelderly and venlafaxine in adults were shown to be efficacious in all age-groups.
Children experienced the maximum benefit and the elderly only marginal benefit
following 6 weeks of treatment.19,20 Adults and the elderly had significant benefit fromantidepressant treatment in terms of reduction of suicidal thoughts and behavior;
however, this improvement was mediated by a decrease in depressive severity. Figure
4 reveals that over time in both treated and control patients, there was a decrease in
the frequency of suicidal thoughts and behavior; however, the decrease wassignificantly more pronounced in patients randomized to antidepressant treatment.
The magnitude of the difference between active treatment and control in terms ofsuicidal thoughts and behavior increases over time in adults and the elderly; however,there was no effect of treatment on suicidal thoughts and behavior in children, despite
statistically and clinically significant benefits in terms of depression observed withactive treatment. These findings suggest that suicidal thoughts and behavior in adults

are largely driven by depression severity; however, this does not appear to be thecase for children.
Clinicians who treat adults need to focus on maximizing the degree of improvement indepression to maximize the decrease in suicidal ideation and thereby acute suicide
risk. These findings are consistent with a recent report in which most suicidal
adolescents (more than 80%) received some form of mental health treatment, but suchtreatment failed to prevent suicidal behavior from occurring.21
What happened following the black box warning?
warning?
Ecological studies revealed that there may have been unintended consequences ofthe black box warning. Evidence now shows that antidepressant prescription rates
dropped precipitously beginning with the public health advisory in March 2004, which
preceded the black box warning in October 2004. Since the initial public healthadvisory, antidepressant prescriptions for children and adolescents decreased, with aconsequent increase (14%) in incidence of suicide in these populations.22,23 No increasein suicide was found in the elderly, for whom antidepressant prescription rates
continued to increase.
Libby and colleagues24,25 found significant decreases in the number of new cases ofchild and young adult depression that were diagnosed by general practitioners
following the black box warning (44% reduction in pediatric patients and 37% in young
adults). Isacsson and Ahlner26 looked at 845 suicides in the 10- to 19-year-old groupin Sweden from 1992 through 2010. After the 2004 warning, the suicide rate increased
for 5 consecutive years (60.5%), largely in those who were not treated withantidepressants.
Busch and colleagues27 studied academic and behavioral outcomes in more than
100,000 adolescents aged 12 to 17 using a difference-in-difference design. They
found that grade point averages (GPAs) for depressed children decreased 0.20 points
following the black box warning in the US; however, there was no change in GPAs in
non-depressed children. They also found increases in delinquency and use of tobaccoand illicit drugs among depressed adolescents.
The FDA implementation of a black box warning had the purpose of reducing suicide
rates in children, adolescents, and young adults. The picture following the FDA
warning and implementation of the black box warning is not that of a lower suicide rate

as intended or hoped for by the FDA. Instead, we see fewer antidepressantprescriptions, an increase in youth suicides, and negative effects on human capital.
That outcome is difficult to reconcile with a model of an increase in youth suicide risk
when antidepressants are prescribed. The findings fit better with a model of a net
reduction in suicide risk when antidepressants are prescribed.
Summary
The data show that in adults, antidepressants appear to protect against suicidal
events. SSRIs are associated with lower overall suicide rates compared with otherclasses of antidepressants (eg, TCAs). Antidepressants are effective in reducing
symptoms, which, in turn, mediates suicidal events in adults and the elderly. This does
not appear to be the case for youths, for whom antidepressant medications can
reduce the severity of depression but appear to have no effect one way or the otheron suicidal thoughts and behavior. Conversely to what is seen in adults, it may be that
aggressive-impulsive traits play a more important role in youth suicide than does
depressed mood. The impact of antidepressants on these traits remains unclear.
Youth suicide may also be potentially related to illicit drug use and social factors, suchas bullying, that are not directly affected by antidepressants.
The black box warning and the earlier public health advisory have shown that
discouraging the medication treatment of depression in children is not an effective
solution in preventing suicidal behavior. Careful monitoring and treatment ofdepression and monitoring suicide risk in children is clearly essential. Overall, theclinical evidence is that the majority of patients, young and old, benefit fromantidepressants, without increased risk of suicide.
Ten years after the introduction of the black box warning, it is time that the FDA
reevaluates this decision and that the results be made public. Moreover, the labelinglanguage should be rewritten to clearly delineate the risks of treatment compared withthe risks of no treatment.

Disclosures
Dr Gibbons is Professor of Biostatistics in the departments of medicine, public healthsciences, and psychiatry, and Director of the Center for Health Statistics at theUniversity of Chicago. Dr Mann is the Paul Janssen Professor of Translational
Neuroscience in the department of psychiatry at Columbia University, and Director,
Molecular Imaging and Neuropathology Division, the New York State PsychiatricInstitute, New York. The authors report no conflicts of interest concerning the subject
matter of this article.

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