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Effect of antidepressants on suicide risk in adults

AUTHOR: A John Rush, MD
SECTION EDITOR: Peter P Roy-Byrne, MD
DEPUTY EDITOR: David Solomon, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2024.

This topic last updated: Dec 21, 2023.

INTRODUCTION

Antidepressants are efficacious for treating depressed patients, especially patients who are
severely ill and may be at greater risk for suicide [1-3]. However, all antidepressants in the
United States carry a warning that they are associated with an increased risk of suicidality in
adults age 18 to 24 years during initial treatment (generally the first one to two months) [4].
Suicidality includes suicidal ideation, action to prepare for an attempt, attempt or nonfatal self-
harm, or death. The warning also applies to children and adolescents.

This topic reviews whether antidepressants affect the risk of suicidality in adults. The effect of
antidepressants on suicide risk in children and adolescents, risk factors and management of
suicidality in adults, and the pharmacology and use of antidepressants to treat depression are
discussed separately.

● (See "Effect of antidepressants on suicide risk in children and adolescents".)

● (See "Suicidal ideation and behavior in adults".)
● (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and
side effects".)
● (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)
● (See "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and
side effects".)
BACKGROUND

In 1990, concerns were first raised about antidepressants precipitating suicidality (ie, suicidal
ideation, action to prepare for an attempt, attempt or nonfatal self-harm, or death). At that
time, case reports described patients who developed intense suicidal ideation during treatment
with fluoxetine, a selective serotonin reuptake inhibitor [5]. The manufacturer of fluoxetine
subsequently performed a meta-analysis of 17 randomized trials (3065 patients with major
depression) and found that the pooled incidence of the combined outcome of preparatory acts,
nonfatal self-harm, or death did not differ significantly between patients who received
fluoxetine or placebo (0.3 versus 0.2 percent) [6]. In addition, baseline suicidal ideation
improved significantly more with fluoxetine than placebo (72 versus 55 percent).

Concerns about antidepressants and suicidality reemerged in 2003 when the US Food and Drug
Administration (FDA) issued an advisory in response to numerous reports of suicidal ideation,
suicide attempts, and suicide deaths in clinical trials of antidepressants in pediatric patients
with unipolar major depression [4,7]. In 2004, the FDA reexamined data from pediatric
randomized trials of the antidepressant drugs bupropion, citalopram, escitalopram, fluoxetine,
fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine. The analyses
suggested an increased risk of suicidal ideation, preparatory acts for self-harm, or nonfatal self-
harm occurring during the first weeks of treatment with an antidepressant, compared with
placebo. As a result, the FDA elevated the advisory and issued a warning regarding emergence
of suicidality in children and adolescents starting antidepressant treatment [4,8].

The FDA issued an advisory in 2005 about suicidality in adults treated with antidepressant drugs
[4]. In 2007, the FDA extended the 2004 warning about antidepressant drugs and suicidality to
include adults age 18 to 24 years and all antidepressant drugs. The warning issued in 2007 did
not advise against the prescription of antidepressants for approved indications, including
depressive and anxiety disorders. Instead, the warning emphasized that:

● Patients 18 to 24 years of age should be informed about the risk of developing suicidality
during initial antidepressant treatment (generally the first one to two months).

● Clinicians should monitor patients closely during initial antidepressant treatment.

● Depression and certain other serious psychiatric disorders are themselves associated with
an increased risk of suicidality.

Although the risk of suicidality posed by antidepressants remains in question, there is no doubt
about the risk of suicidality in untreated depressed patients [9]. As an example, an
observational study of 186 depressed patients followed for up to 38 years found that 14 percent
committed suicide, which was 27 times greater than the rate in the general population;
treatment with an antidepressant was associated with a lower rate of suicide mortality. [10].

There is no evidence that more frequent contact between clinicians and depressed patients
reduces the risk of suicide attempt or suicide death. However, there is evidence that fewer
symptoms of depression occur in patients who receive follow-up care, compared with patients
who do not [11]. Advisories and warnings about the need for more frequent monitoring do not
seem to have increased the low rate of follow-up care during antidepressant treatment [12].

EVIDENCE REVIEW

Overview — There is no clear evidence that treatment of depressed patients with

antidepressant drugs increases the average risk of suicidality (ie, suicidal ideation, action to
prepare for an attempt, attempt or nonfatal self-harm, or death) [9,13]. However, there may be
an age-specific effect, such that antidepressants may raise the risk of suicide attempts (nonfatal
self-harm) or preparatory acts in patients age 18 to 24 years during the first several weeks of
treatment, yet have no effect upon patients age 25 to 30 years, and may lower the risk in
patients 31 years and older. It is not known whether there are other sociodemographic or
clinical factors associated with risk of suicidality in patients treated with antidepressants. In
addition, it is not known whether specific antidepressant drugs differ in their risk of suicidality,
or how polypharmacy affects the risk.

Several methodologic issues make it difficult to answer the question of whether

antidepressants cause suicidality. The associations between depression and use of
antidepressants and between depression and suicidality potentially confound the results of
studies that examine the association between antidepressants and suicidality [14]. Another
issue is the reliability of classifying certain events or behavior as suicide attempts [15]. (See
'Methodologic issues' below.)

Three types of studies have examined the association between antidepressants and suicidality.
In order of quality, these are [16]:

● Randomized trials (including meta-analyses)

● Observational studies (including meta-analyses)
● Ecological studies (these use community-level, epidemiologic data rather than individual-
level data)

Randomized trials
 Suicide deaths — Three independent analyses combined data from placebo-controlled
efficacy trials of various antidepressants to examine risk of suicide death during antidepressant
treatment [17-19]. Each analysis found no evidence for higher or lower risk of suicide death
during acute-phase treatment with antidepressants compared with risk during treatment with a
placebo.

● A meta-analysis of 342 randomized trials (40,826 patients) found no significant difference

in suicide deaths for patients treated with a selective serotonin reuptake inhibitor (SSRI)
compared with patients treated with placebo (0.04 versus 0.04 percent) [18].

● A meta-analysis of 207 randomized trials (40,028 patients) found no significant difference

in suicide deaths for patients treated with an antidepressant compared with patients
treated with placebo [19].

● A secondary analysis of 48,277 depressed patients found no significant difference in

suicide deaths for patients treated with an SSRI, a non-SSRI antidepressant, or placebo
(0.15 versus 0.20 versus 0.10 percent) [17].

It should be noted that the data used in these analyses were often overlapping, rather than
independent.

New onset of suicidal behavior — Five re-analyses of data from randomized trials suggested
that treatment with antidepressants was associated with an increased risk of nonfatal self-harm
(attempt) or preparatory acts, compared with placebo [18,20-23]. The increased risk appeared
to reside primarily in patients under the age of 25 years.

● Two meta-analyses (n >40,000 and 36,000 patients) focused on SSRI antidepressants and
found that the risk of nonfatal self-harm was 1.6 to 2.3 times higher during the first weeks
of SSRI treatment compared with treatment with placebo [18,20].

● A meta-analysis (372 trials, n >99,000 patients) found that the relative odds of nonfatal
self-harm and preparatory acts varied by age. Compared with the risk during placebo
treatment, the risk of nonfatal self-harm and preparatory acts during antidepressant
treatment was [21]:

• More than twice as high in patients under age 25 years (absolute difference
approximately 4 per 1000 patients)

• Approximately equal in patients age 25 to 64 years

 • Approximately half as high in those age 65 or more years (absolute difference
approximately 3 per 1000 patients)

● A meta-analysis of 70 trials (n >18,000 patients) compared antidepressants (duloxetine,

fluoxetine, paroxetine, sertraline, or venlafaxine) with placebo on the outcome of
suicidality, which included suicide, suicide attempt or preparatory behavior, intentional
self-harm, and suicidal ideation [23]. The results indicated that suicidality varied by age:

• Among adults (age ≥18 years), suicidality was comparable in patients who received
antidepressants and placebo (odds ratio 0.8, 95% CI 0.5-1.3).

• Among children and adolescents, antidepressants doubled the risk of suicidality (odds
ratio 2.4, 95% CI 1.3-4.3).

Given the higher frequency of suicide attempts than suicide deaths, these analyses had
adequate statistical power to detect effects of treatment with antidepressants overall or with a
commonly used class of drugs (such as SSRIs). It appears that there is no difference in risk of
suicide attempts among different classes of antidepressants. (See 'Differences among
antidepressant classes' below.)

The analyses did not have adequate power to either detect or exclude even relatively large
effects of individual antidepressant drugs. In addition, data from these trials could not be used
to examine the effect of antidepressants on reducing baseline nonfatal self-harm or
preparatory acts, because patients with such behavior were typically excluded from such trials.

New onset of suicidal ideation — Among patients with no suicidal ideation at the start of
treatment, antidepressants do not increase the incidence of suicidal ideation:

● A pooled analysis of four randomized trials (n = 1399 patients with unipolar major
depression) found that in patients with no suicidal ideation at baseline, new onset of
suicidal thoughts was comparable with vilazodone and placebo (9 and 10 percent) [24].

● A pooled analysis of three randomized trials (n = 1374 patients with generalized anxiety
disorder) found that in patients with no suicidal ideation at baseline, new onset of suicidal
thoughts was comparable with vilazodone and placebo (4 and 6 percent) [24].

● A pooled analysis of four randomized trials (n = 1603 patients with unipolar major
depression) found that in patients with no suicidal ideation at baseline, new onset of
suicidal thoughts was comparable with levomilnacipran and placebo (11 and 9 percent)
[25].
 Reduction of existing suicidal ideation — Among patients with suicidal ideation at the start
of treatment, antidepressants reduce suicidal thoughts and behavior:

● A meta-analysis of patient level data (37 randomized trials, 8477 adult and geriatric
patients with unipolar major depression) compared fluoxetine (modal dose 20 mg per day)
or venlafaxine (modal dose range 75 to 150 mg per day) with placebo [26]. The risk of
suicidal thoughts and behavior over 12 weeks decreased more with active treatment than
placebo; the effect appeared to be mediated by decreases in depressive symptoms.

● An eight-week randomized trial compared paroxetine (mean dose 39 mg per day) with
placebo in 173 patients with unipolar major depression and found that suicidal ideation
improved more with paroxetine, and the effect was clinically large [27].

Suicidality — The composite outcome of suicidality includes suicidal ideation, preparatory act,
nonfatal self-harm or attempt, or death. Randomized trials indicate that antidepressants do not
increase the risk of suicidality in adults. In a meta-analysis of 32 randomized trials (n >8,000
adults) that compared duloxetine, fluoxetine, paroxetine, sertraline, or venlafaxine with placebo,
suicidality was comparable for active treatment and placebo (odds ratio 0.8, 95% CI 0.5-1.3) [23].

Suicidality and age — New onset of suicidality (suicidal ideation, preparatory act,
nonfatal self-harm or attempt, or death) was evaluated in separate meta-analyses of
randomized trials in adults as well as children and adolescents. Taken together, the findings
showed a convincing trend of increasing risk in younger age groups, and decreasing risk in
older adults ( figure 1) [9,13]. The pattern is striking, though in itself does not constitute
proof:

● Children and adolescents (odds ratio 2.22, 95% CI 1.40-3.60)

● Age 18 to 24 years (odds ratio 1.55, 0.91-2.70)
● Age 25 to 30 years (odds ratio 1.00, 0.60-1.69)
● Age 31 to 64 years (odds ratio 0.77, 0.60-1.00)
● Age ≥65 years (odds ratio 0.39, 0.18-0.78)

Studies of individual drugs show a similar trend of increasing risk with younger age. As an
example, a meta-analysis of 61 randomized trials (14,911 adult patients with various psychiatric
disorders) found that suicidality did not differ significantly between paroxetine compared with
placebo (0.9 versus 1.1 percent of patients) [28]. However, a separate analysis of adults age 18
to 24 years found a nonsignificant, twofold increase in suicidality with paroxetine compared
with placebo (2.6 versus 1.3 percent of patients; odds ratio 2.0, 95% CI 0.8-4.8). By contrast, the
analysis of adults age 25 to 64 years found a nonsignificant decrease in suicidality with
paroxetine compared with placebo (0.8 versus 1.1 percent of patients; odds ratio 0.7, 95% CI
0.5-1.0).

Methodologic issues — The evidence available for examining whether antidepressants cause
suicidality in adults is imperfect [16]. The highest quality of existing evidence consists of meta-
analyses of data from secondary analyses of randomized efficacy trials.

The question about whether antidepressants precipitate suicidality should ideally be answered
with placebo-controlled trials specifically designed to address this issue. However, no such trials
exist and it would not be feasible to assign depressed patients to a long-term placebo arm.
Instead, we must rely upon secondary analyses of trials designed to evaluate clinical efficacy
and medical adverse events. Our ability to answer the question with these analyses is restricted
by certain factors. First, patients at high risk for suicide attempts are typically excluded from
such trials (limiting external validity or generalizability) [16]. Thus, data from such trials are
limited in their capacity to detect change in suicidality and, in addition, cannot address the
patients about whom we are most concerned. A second limitation of existing trials is that
assessments were not designed to identify emergence or worsening of suicidal ideation.
Consequently, reanalyses of those data depend on post-hoc classification of measurements
intended for a different purpose. Third, although most trials involved patients with depression,
some trials involved other psychiatric illnesses, such as anxiety disorders. Fourth, trials were
short-term in duration, lasting approximately six to eight weeks.

Suicide deaths are relatively rare events in randomized trials, and there were typically fewer
than 100 completed suicides for all drugs and placebo combined in the meta-analyses.
Although the analyses included hundreds of trials and tens of thousands of patients, statistical
power to detect differences in suicide mortality rates was modest. Thus, none of the analyses
could rule out relatively large (ie, three- or fourfold) increases or decreases in risk of suicide
mortality during antidepressant treatment compared with placebo. In addition, randomized
trials will most likely never have sufficient statistical power to examine suicide mortality with
specific antidepressant drugs.

Observational studies — Observational (cohort and case-control) studies suggest that

treatment of depressed patients with an SSRI is associated with fewer suicide attempts or
suicide deaths, compared with no treatment with an antidepressant [29-33]. In addition,
symptom severity and the rate of suicide attempts appear to be higher during the time period
preceding antidepressant treatment, compared with post-treatment.

Suicide death or attempt — Many observational studies suggest that antidepressants are not
associated with an increased risk of suicidal behavior in adults [30,33,34]:
 ● A retrospective study of an administrative claims database in the United States examined
suicide attempts in patients with a new episode of depression who were treated with
antidepressants (n >100,000) or were not treated with antidepressants (n >200,000) [35].
After adjusting for the probability (propensity) to receive antidepressants, based upon
potential confounding factors such as depression severity, history of suicide attempt, and
comorbid general medical and psychiatric diagnoses, the analyses found that suicide
attempts were comparable for the treated and untreated groups.

● A retrospective study used an administrative claims database to examine the use of

antidepressants and the number of suicide attempts that occurred before and after the US
Food and Drug Administration (FDA) issued its warnings about a possible increased risk of
suicidal ideation and behavior due to antidepressants [36]. The dataset included a cohort
of young adults age 18 to 29 years (n = 1.4 million). Psychotropic drug poisonings was
used as a proxy for suicide attempts. The study found that in the second year (2006) after
the warnings, use of antidepressants declined by 24 percent, whereas psychotropic drug
poisonings increased by 34 percent. It is worth noting that psychotropic poisonings may
include accidental overdoses as well as suicidality.

● A meta-analysis of eight observational studies (n >250,000 depressed patients treated with

an SSRI) found that use of an SSRI was associated with a decreased risk of suicide death or
attempt, compared with no antidepressant treatment in controls (odds ratio 0.6, 95% CI
0.5-0.7) [29]. The protective effect was larger in patients age 65 years or more (odds ratio
0.5).

● Data from multiple health care systems, which studied depressed patients treated with
antidepressants (n >70,000 [30], n >110,000 [32], and n >50,000) [35], all found the same
pattern: suicide attempts were higher in the month before starting antidepressant
medication and declined after starting medication.

Methodologic problems — Relative strengths and weaknesses of large observational studies

are opposite those of randomized trials. Data from large population-based samples increase
statistical power and maximize generalizability. However, nonrandom assignment of treatments
introduces bias and threatens internal validity, especially if treatment decisions (such as the
decision to prescribe an antidepressant or the choice of specific antidepressant) are influenced
by clinical characteristics related to risk of suicidality. As an example, SSRIs are safer in overdose
than tricyclic antidepressants, and clinicians may thus be more likely to prescribe SSRIs to
patients who present with suicidality.
Ecological studies — Ecological studies used community-level, epidemiologic data to examine
whether variation in rates of antidepressant use (either between areas or over time) were
associated with variation in suicide deaths. Most studies found that higher rates of
antidepressant use were associated with lower rates of suicide death [37-40]:

● A cross-sectional analysis of county-level data from the United States found that use of
either an SSRI or other antidepressant (nefazodone, mirtazapine, bupropion, or
venlafaxine) were each associated with lower suicide mortality [37].

● An increase of antidepressant use by 161 percent over a seven-year period in a district of

Sweden was accompanied by a 36 percent decrease in the rate of suicide death [40].

● Analyses of time trends prior to the FDA warnings found that increasing rates of
antidepressant use in England and Japan were accompanied by declines in suicide
mortality [38,39].

● In a study that examined antidepressant prescribing rates and suicide rates across 29
European countries, increased use of antidepressants was associated with decreased
suicides [41].

However, other ecological studies have found that antidepressant use was not associated with
suicide rates [42].

These ecological studies cannot determine whether differences in suicide deaths are the direct
result of differences in antidepressant use or whether differences in antidepressant use are
simply a marker for other “true” causes of lower suicide rates (such as better recognition and
treatment of depression).

Several observational studies have focused upon the effects of FDA safety advisories on
antidepressant prescribing and suicidal behavior. These studies have generally found that
safety advisories and the accompanying publicity were followed by decreases in rates of
depression diagnosis and antidepressant prescribing, especially among adolescents and young
adults [36,43-45]. Some studies also found evidence for increased rates of suicide attempts or
psychotropic drug poisoning [36,45]. All of this research, however, is more relevant to policy
questions regarding safety warnings than to the true causal relationship between starting
antidepressant treatment and subsequent suicidal ideation or behavior. Whether or not
antidepressant drugs sometimes precipitate suicidal ideation or behavior, policy changes (such
as safety warnings) can have both intended and unintended consequences.
Differences among antidepressant classes — Concern about antidepressants and suicidality
were first raised in regard to the SSRI fluoxetine [5], and the FDA warning about antidepressants
and suicidality initially focused upon SSRIs and bupropion, mirtazapine, nefazodone, and
venlafaxine [8]. The warning now extends to all antidepressants. Although a few observational
studies suggest that some antidepressants are associated with higher rates of suicide deaths
and attempts [46,47], most randomized trials and observational studies suggest that there is no
difference in risk of suicidality among different classes of antidepressants, including SSRIs,
serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase
inhibitors, and other antidepressants (bupropion, mirtazapine, and nefazodone) [6,17]:

● A meta-analysis of randomized trials found that the risk of nonfatal self-harm was
comparable for SSRIs and tricyclic antidepressants [20].

● Multiple observational studies from different countries have found that different classes of
antidepressants are associated with a comparable risk of suicide attempts and deaths [48-
52]. One observational study using electronic health records data found that the risk of
self-harm was greater in patients starting treatment with mirtazapine, trazodone, or
venlafaxine, compared with patients starting treatment with citalopram [46]. However,
another records-based study, which used propensity scoring to account for observed
potential confounders, found that self-harm was comparable across individual drugs as
well as drug classes [35].

Available evidence is not adequate to determine the risk associated with specific antidepressant
drugs.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Depressive disorders".)

SUMMARY

● Background – The US Food and Drug Administration (FDA) issued a warning in 2007 that
patients age 18 to 24 years should be informed about the risk of becoming suicidal during
initial treatment with any antidepressant drug, that clinicians should monitor patients
closely during initial antidepressant treatment, and that depression and other serious
psychiatric disorders are themselves associated with an increased risk of suicide. The
 warning does not advise against the use of antidepressants for approved indications,
including depressive and anxiety disorders.

The small risk of suicidality in young adults associated with antidepressants needs to be
balanced against the clear risk of suicidality associated with depressive syndromes. (See
'Background' above.)

● Evidence

• Overview – There is no clear evidence that antidepressant treatment of depressed

patients increases the risk of suicidality (suicidal ideation, action to prepare for an
attempt, attempt or nonfatal self-harm, or death) in adults. Randomized trials suggest
that antidepressants do not increase the risk of suicidality; some observational and
ecological studies show an association between greater antidepressant use and
decreased suicide attempts and suicide deaths. (See 'Overview' above and 'Suicidality'
above and 'Observational studies' above and 'Ecological studies' above.)

• Suicidality and age – Available evidence strongly suggests an age-specific effect of

antidepressants and risk of suicidality. Among young adults (and children and
adolescents), onset of suicidality is significantly greater compared with placebo.
However, the same evidence shows no detectable effect of antidepressant treatment
on suicidality in middle-aged adults, and suggests a protective effect (lower risk of
suicidality with antidepressant medication than with placebo) among older adults. (See
'Suicidality and age' above.)

• Differences among antidepressant classes – Randomized trials and most

observational studies suggest there is no difference in risk of suicidality among
different classes of antidepressants, including selective serotonin reuptake inhibitors,
serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine
oxidase inhibitors, and other antidepressants. Available evidence is not adequate to
determine the risk associated with specific antidepressant drugs. (See 'Differences
among antidepressant classes' above.)

ACKNOWLEDGMENT

The UpToDate editorial staff acknowledges Gregory Simon, MD, MPH, who contributed to an
earlier version of this topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 14672 Version 23.0
GRAPHICS

Age-specific odds ratios for suicidal ideation and behavior

* Odds ratios >1.0 indicate that the risk of suicidality while receiving antidepressants is elevated relative
to placebo; odds ratios <1.0 indicate a protective effect of antidepressants.

Reprinted with permission from: the American Journal of Psychiatry (Copyright © 2007). American Psychiatric Association.

Graphic 63706 Version 6.0

Contributor Disclosures
A John Rush, MD Patent Holder: Methods to Identify Patients at Risk of Developing Adverse Events
During Treatment with Antidepressant Medication [Patent 7,906,283]; Methods to Predict the Outcome of
Treatment with Antidepressant Medication [Patent 7,795,033]. Consultant/Advisory Boards: Compass
[Psilocybin]; Emmes Corp [Substance use disorder]; Evecxia Therapeutics, Inc [Depression]; Holmusk
Technologies, Inc [Depression]; ICON plc [Depression]; Johnson and Johnson [Ketamine]; Liva-Nova
[Depression]; MindStreet [Depression]; Neurocrine Biosciences Inc [Depression]; Otsuka-US [Depression].
Speaker's Bureau: Johnson and Johnson [Depression]; Liva-Nova [Depression]. Other Financial Interest:
Guilford Press [Royalties]; UT Southwestern [Royalties]. All of the relevant financial relationships listed have
been mitigated. Peter P Roy-Byrne, MD No relevant financial relationship(s) with ineligible companies to
disclose. David Solomon, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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