Safe use of SSRIs in young adults: How strong is evidence for new suicide warning?

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Safe use of SSRIs in young adults: How strong is evidence for new suicide warning?
Author(s)
Michael F. Grunebaum, MD
John J. Mann, MD

CASE: Life is 'not worth it'

Mr. B, age 20, has taken a semester leave from college because of gradually worsening depressed mood. Over the past 2 months he has lost interest in jogging and playing piano—which he usually enjoys. He reports reduced libido, middle insomnia, loss of appetite, feeling as if his head is “full of cotton,” trouble concentrating, and waking in the morning with a sense of dread. His anxiety dissipates during the day, but he continues to feel sad and sometimes weepy, which is unusual for him.

Clinical Point

In 2003 to 2004, after the ‘black-box’ warning, pediatric antidepressant prescriptions declined and suicide rates increased 11%

Mr. B reports feeling hopeless at times and has had vague thoughts about life being “not worth it if I continue to feel like this” but denies specific suicide plans. Your initial impression is that Mr. B is in the midst of a major depressive episode and that a selective serotonin reuptake inhibitor (SSRI) is indicated. As you finish taking his history, you run through your mind the pros and cons of the recommendation you will make to him.

Do SSRIs raise or lower the risk for suicidal behavior in young adults such as Mr. B? The answer is complicated and goes beyond an “either/or” question, as the FDA acknowledged in May 2007 when it:

  • extended the black-box warning of increased suicidality risk with antidepressants to cover adults age 18 to 24 as well as children and adolescents
  • included language in the warning about the benefits of treating depression and the suicide risk associated with untreated depression, given concerns about declining antidepressant prescriptions and rising suicides among youth.1
  • To help you make informed decisions when treating depression in adults, this article reviews the studies leading up to and following the FDA’s meta-analysis of antidepressant trial data in patients age 18 and older. Our goal is to provide a framework for clinical treatment of adults age 18 to 24 and those age ≥25.

Box

FDA’s pediatric suicidality analysis: What the data showed

The FDA meta-analysis designed to investigate a reported association between antidepressants and suicidality in children and adolescents found contradictory results:

  • Pooled adverse event data from 24 pediatric antidepressant trials totaling >4,400 patients showed a higher risk of suicidal ideation or behavior (no suicides occurred) with antidepressants (4%) vs placebo (2%).
  • Systematically collected suicide-related item scores from 17 of the trials showed no evidence that antidepressants worsen suicidality or cause it to emerge.

One interpretation of these findings is that antidepressants’ effect on suicidality is small and therefore subject to measurement error.

Another is ascertainment bias; any side effect associated with active medication encourages discussion with the clinician and may distort the frequency of reported adverse events.

The FDA meta-analysis also found:

  • Relative risk for suicidality ranged 10-fold among agents, from 0.9 with fluoxetine to 8.8 with venlafaxine.
  • Most suicide-related events occurred in subjects having the highest baseline levels of suicidality.
  • Hostility and agitation emerged with SSRI use, particularly during the first month of treatment.
  • Patient age, sex, or history of suicide attempt/ideation did not affect the results.

Source: Reference 7

First hints of suicidality

SSRIs revolutionized depression treatment. From 1985 to 1999, annual U.S. antidepressant prescriptions quadrupled, with SSRIs accounting for 70% of the increase (see “Antidepressants and suicide risk, 1985 to 2007”). At the same time, the age-adjusted suicide rate:

Clinical Point

FDA’s meta-analysis of suicide risk in adults found 8 suicides in 372 antidepressant trials totalling nearly 100,000 persons

  • dropped 22.5% for women (who account for twice as many antidepressant prescriptions as men)
  • dropped 12.8% for men (without change in the rank order of suicide methods).2
For many patients, increased antidepressant use improved treatment of major depressive and other antidepressant-responsive disorders. In 1990, however, case reports suggested SSRIs might cause suicidal thoughts or behavior.3 Hypothesized mechanisms included increased aggression4 and akathisia.5 An FDA review found no proof, and a meta-analysis of data from 17 double-blind, randomized, controlled trials found no association between fluoxetine and suicidal thoughts or behavior.6

The debate rekindled in June 2003 when the British Committee on Safety of Medicines warned against using paroxetine or venlafaxine in children. After conducting its own meta-analysis, the FDA in 2004 ordered a black-box warning about suicidality and the use of antidepressants in children and adolescents ( Box ).7

After the pediatric ‘black box.’ Antidepressant prescriptions for children and adolescents declined in the years 2003 to 2004, as did diagnosis of pediatric depression.8-10 Antidepressant prescribing also showed signs of shifting from general practitioners to psychiatrists.8 At the same time, the suicide rate among youth age 11 In patients age >60, SSRI prescriptions continued to rise and suicide rates fell,9 a pattern of change consistent with antidepressants protecting against suicide.

 

 

An independent meta-analysis by Bridge et al12 examined the pediatric trial data used in the FDA meta-analysis plus 7 additional studies. Its findings differ in 2 important ways from those of the FDA review:

  • Antidepressants—including others besides fluoxetine—showed efficacy in treating anxiety disorders and depression in children and adolescents.
  • The frequency of suicide-related adverse events (no trial patients committed suicide) was approximately 3% on active medication—25% lower than the FDA estimated rate—and 2% on placebo, similar to the FDA estimate.
The number needed to treat (NNT)— number of patients who must be treated to get a therapeutic response that would not have happened with placebo—ranged from 3 to 10. The number needed to harm (NNH)—number of patients who must be treated for 1 suicidal ideation/nonfatal attempt to occur that would not have happened with placebo—ranged from 112 to 200. The authors interpreted this as “indicating a favorable overall risk-to-benefit profile for antidepressants in the treatment of pediatric [major depressive disorder], [obsessive-compulsive disorder] (OCD), and non-OCD anxiety disorders.”12 These findings appear to support the efficacy of antidepressants in pediatric patients and a favorable risk-benefit ratio.

Antidepressants and suicide risk, 1985 to 2007

19851990199119992003200420062007
 Case reports suggest link between suicide and SSRI useFDA analysis finds no association between SSRIs and increased suicide risk UK agency warns of suicide-related events in children treated with paroxetine and venlafaxineFDA conducts meta-analysis, requires black-box warnings of risk of suicidality in youth taking antidepressantsFDA meta-analysis finds age-dependent effect of antidepressants on suicidality risk in adultsFDA expands warning of increased suicidality risk with antidepressants to adults age
Antidepressant prescriptions quadruple; age-adjusted suicide rate drops 22.5% for women and 12.8% for menPediatric depression diagnoses and antidepressant prescriptions decline; suicides increase 11%Bridge et al meta-analysis finds 25% lower rate of suicide-related events in youth than the FDA found

What about adults?

Overall effect. A subsequent FDA meta-analysis of antidepressant clinical trial data in adults13 found 8 suicides in 372 trials totaling nearly 100,000 persons. All occurred in the 295 trials with psychiatric indications. Among these psychiatric trials, 59% had a suicidal behavior/ideation event in either the test-drug or placebo arm, and 41% had none. Eleven antidepressants were included in the meta-analysis:

Clinical Point

Antidepressants’ antisuicidality benefit appears greater for patients age ≥ 25 than for those age 18 to 24

  • 6 SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
  • 2 SNRIs (duloxetine and venlafaxine)
  • 3 others (bupropion, mirtazapine, and nefazodone).
Overall, antidepressants showed a protective (antisuicidal) effect in adults as compared with placebo (odds ratio 0.85 [95% CI: 0.71 to 1.02, P=0.08]), with no difference in effect between SSRIs and non-SSRIs.

Age-specific findings. When the FDA analysis was stratified by age, however, antidepressants’ benefit appeared greater for patients age ≥25 than for those age 18 to 24. The data suggested:

  • elevated suicidality risk among adults age
  • neutral or possibly protective effect for adults age 25 to 64
  • protective effect in adults age ≥65 ( Table 1 ).13
Table 1

FDA meta-analysis: Suicide rates by age in antidepressant trials

Age group (yr)Suicide rate (%)(test drug/placebo)Suicide attempt rate (%)(test drug/placebo)
18 to 240.03/0.000.55/0.27
25 to 300.00/0.030.23/0.11
31 to 640.01/0.000.13/0.15
≥650.00/0.040.03/0.25
Source: Reference 13
For 18-to 24-year-olds, the suicide rate was 0.03% (~1/4,000) in these mostly 8- to 12-week trials, and the suicide attempt rate was 0.55% (~1/200). For comparison, the lifetime prevalence of suicide was 2.2% to 8.6%—depending partly on illness severity—in a meta-analysis of patients with mood disorders.14

The odds ratio for suicidal behavior (preparatory acts, attempt, or suicide) for subacts, attempt, or suicide) for subjects age 18 to 24 on test drug vs placebo was 2.31 (95% CI: 1.02, 5.64) [event rate/sample: 23/3810 vs 8/2604]. NNH was 333, which means 333 adults in this age group would need to be treated with an antidepressant for 1 to experience a suicidal behavior event that would not have happened with placebo.

Clinical Point

Suicide attempt rates decline steadily after antidepressant or psychotherapy begins in depressed adults (including those age Compare an NNH of 333 with the much lower NNH values associated with antiarrhythmic treatment of atrial fibrillation (AF),15 an important cardiovascular cause of morbidity and mortality. A meta-analysis of 44 AF trials totalling 11,322 subjects found that—although “moderately effective” for maintaining sinus rhythm—all but 2 of the 10 drugs were pro-arrhythmic. Their NNH values of 17 to 119 are, at best, approximately one-third the NNH for antidepressants for suicidality in young adults based on adverse event reports. With NNH, higher is safer.

The age-related pattern the FDA found in its adult meta-analysis ( Table 2 )13 is consistent with its earlier pediatric analysis7 but not with the more recent findings of Bridge et al12 that included a larger data set.

Table 2

FDA meta-analysis: Risk of suicidality in adults taking antidepressants

Protective benefit appeared greater for dults age ≥25 than for those age 18 to 24
Elevated risk appeared to apply to adults age
A “slight suggestion” of increased risk was seen with SNRIs vs other classes, but no significant differences among drugs or drug classes
Risk was increased in adults who did not respond to active drug treatment
Risk was not affected by patient sex, race, geographic location, inpatient vs outpatient care, or treatment with SSRIs vs non-SSRIs
Risk may be lower with sertraline than with other antidepressants, although this trend could be a false-positive result related to multiple tests
A “sensitivity analysis” using alternate statistical methods to test the robustness of the findings yielded similar results
SNRIs: serotonin-norepinephrine reuptake inhibitors;
SSRIs: selective serotonin reuptake inhibitors
Source: Reference 13

Mixed evidence

Aside from the FDA meta-analysis,13 what is the evidence that antidepressants—or specifically SSRIs—may cause suicidality in adults? Among 9 major published studies in adults of the relationship between SSRIs and suicidal behavior (deaths or attempts):

Clinical Point

If you decide to prescribe an SSRI for a depressed young adult, start with a low dosage (such as fluoxetine, 10 mg/d) for several days

Table 3A

4 studies found no relationship
between SSRI use and suicide in adults

Study designMain resultsLimitations
Meta-analysis of FDA data by Khan et al;16 >48,000 patients in trials that included fluoxetine, sertraline, paroxetine, citalopramNo difference in suicide rates among SSRIs, other antidepressants, or placeboPatients not representative of general clinical population
Trials mostly short-term; tended to exclude suicidal patients
Case-control study in UK primary care practice by Jick et al;17 antidepressant users, 555 with suicidal behavior vs 2,062 withoutRisk of suicidal ideation or behavior did not differ between SSRIs vs non-SSRIsObservational study
Confounding by indication*
Case-control study in UK primary care practice by Martinez et al;18 >146,000 persons, first antidepressant prescription for depressionNo evidence that risk of suicide or nonfatal self-harm was greater with SSRIs than with tricyclicsObservational study
Confounding by indication*
Meta-analysis in UK by Gunnell et al;19 477 clinical trials (N>40,000) of SSRIs vs placebo in depressionNo evidence that SSRIs increased suicide risk
Weak evidence of increased self-harm risk		Lack of individual or trial-level data
Evidence suggests nonfatal suicidal ideation/self-harm events are underreported
SSRI: selective serotonin reuptake inhibitor; UK: United Kingdom
* Confounding by indication: Clinicians may preferentially prescribe SSRIs to patients thought to be at risk for suicide because of these drugs’ relative safety in overdose.

Table 3B

2 studies found SSRIs may increase suicide risk in adults

Study designMain resultsLimitations
Meta-analysis (1967 to 2003) by Fergusson et al;20 702 trials comparing SSRIs vs placebo or other drug for any condition (N>87,000)Suicide attempts almost twice as likely with SSRIs vs placebo, but no difference in fatal attempts; no difference in risk between SSRIs and TCAsMany methodologic limitations in clinical trials, such as underreporting of suicidal behavior
Limited to public data
Case-control study of geriatric population in Ontario by Juurlink et al;21 1,138 suicides vs 4,552 controls matched for demographic characteristics and antecedent illness patternsSSRIs were associated with higher risk of suicide than other antidepressants during first month of therapy (adjusted OR: 4.8, 95% CI=1.9–12.2)
Risk independent of recent diagnosis of depression or receipt of psychiatric care
Violent suicides more common with SSRIs than other antidepressants
No difference in suicide risk after first month
Absolute risk of suicide with antidepressants was low		Confounding by indication*
14% of suicide sample excluded from analysis
CI: confidence interval; OR: odds ratio; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; UK: United Kingdom
* Confounding by indication: Clinicians may preferentially prescribe SSRIs to patients thought to be at risk for suicide because of these drugs’ relative safety in overdose.

Table 3C

3 studies found SSRIs may lower suicide risk in adults

Study designMain resultsLimitations
Case-control forensic toxicology by Isacsson et al;22 14,857 suicides compared with 26,422 deaths by accident or natural causes in Sweden (1992 to 2000)SSRIs less likely than other antidepressants to be detected in suicide victimsNaturalistic study
Possible residual confounding
Observational study by Simon et al;23 82,285 antidepressant treatment episodes among 65,103 health plan outpatients (1992 to 2003)Suicide risk in acute-phase treatment ~1/3,000; risk of suicide attempt leading to hospitalization ~1/1,000
No increased risk of suicide or serious attempt suggested during first month of treatment
No greater risk seen with newer drugs (mostly SSRIs)
General decline in risk of suicide attempts after starting antidepressant treatment		Potential uncontrolled confounding
Geographically limited sample
Possible misclassification in computerized records
Lack of data on medication adherence
Death certificates may underestimate suicide rates
Observational study by Gibbons et al24 of suicide attempts in veterans treated for depression; 226,866 patients treated with SSRI, other antidepressant, or no antidepressant (2003 to 2004)SSRI treatment associated with ~1/3 lower risk of suicide attempts compared with no antidepressant treatment
Finding consistent in veterans age 18 to 25 and in older veterans		Sample of veterans, 92% male
Dataset did not include suicides, so results pertain only to suicide attempts
SSRIs: selective serotonin reuptake inhibitors

Evidence of protection

Epidemiologic studies. Suicide attempt rates in depressed youth and adults—including those age 25

Evidence from psychological autopsies—which attempt to reconstruct a decedent’s thoughts, feelings, and actions before death—indicates that:

  • Approximately 60% of suicides occur in persons with a mood disorder.26
  • Since the advent of SSRIs, the rate of postmortem detection of antidepressants in suicides has increased from 8% to 15%, whereas the rate of suicide deaths caused by antidepressant overdose remains at approximately 5%.27
Similarly, in 1 suicide study, no antidepressants were detected postmortem in >50% of persons for whom they had been prescribed.28 Systematic review finds substantial literature showing antidepressants’ efficacy for major depressive disorder.29

Population studies in the United States30 and many other31,32 —but not all33 —countries report a correlation between increased antidepressant prescriptions and lower suicide rates. Because of their limitations, however, population studies cannot make a causal connection between antidepressant prescribing and suicide rates.

Randomized, controlled trials (RCTs) reduce sources of bias, but designing an RCT to test whether or not antidepressants prevent suicide is not feasible. Given suicide’s relative infrequency (~11 per 100,000 persons/year in the United States11 ), an RCT would require a sample of many thousands.

Meta-analyses of data pooled from smaller trials—such as the FDA studies of antidepressants and suicidality7,13 —are done to gain statistical power from larger samples, but these also have methodologic limitations ( Table 4 ). Proxy outcomes— such as suicide attempts and ideation in high-risk samples—also can be studied, as we are doing in our clinic (see Related Resources ).

Table 4

SSRIs and suicidality:
Limitations of the FDA’s meta-analyses of pooled data

The pooled clinical trials were not designed to measure suicidality, so relevant data were not collected systematically
Suicidal patients who are most at risk tend to be excluded from industry-sponsored trials
Post hoc analyses of safety and effects on suicidality are subject to limitations of multiple testing and possible false-positives
The FDA “suicidality” outcome variable, which combined suicidal ideation and behavior, is subject to measurement bias. It was constructed after the trials were completed and relied on spontaneously reported adverse events (not systematic assessment). If subjects on active drug had more physical side effects, they might have had greater contact with their physicians and more opportunities to report suicidal ideation or behavior
The pooled trials were conducted over many years and study samples may have changed over time, with later studies enrolling more treatment-resistant subjects

CASE CONTINUED: Hypomanic, or just in love?

Clinical Point

Make weekly contact with the patient by phone or in person for the first few weeks after starting SSRI treatment

Mr. B reports no medical problems and is taking no medications. He talked to a college counselor 3 times during his freshman year when he was upset after a romantic breakup, found it helpful, and says his feelings resolved. He reports trying marijuana and cocaine “a few times.” During his sophomore year he felt very happy and energized about a new relationship for approximately 1 week, but says he was sleeping normally and functioning well in school during that time.

He describes his father as very “serious” and sometimes pessimistic, but he does not know if his father ever had mental health treatment. On mental status exam, Mr. B is neat, cooperative, and looks worried. His speech is slightly labored and ruminative. His psychomotor state is normal. He has no psychotic symptoms, and his cognitive exam is normal. Because he is out of school, he has no health insurance.

Clinical recommendations

Case presentations such as Mr. B’s raise questions you must consider when prescribing SSRIs, particularly to young adults:

Clinical Point

When prescribing SSRIs, assess the patient regularly for suicidal thoughts, hopelessness, substance abuse, and impulsivity

  • Was his “energized” episode a mild hypomanic period or just normal feelings of “being in love”?
  • Is he minimizing substance use, which is a common comorbidity in depressed persons who die by suicide?
  • He has melancholic symptoms; does he have psychotic ruminations he is not sharing?
  • Without health insurance, how frequently will he be able to make follow-up appointments?

Prescribing any antidepressant for a specific patient is a complex, individualized decision based on weighing risks vs benefits. If you decide to prescribe an SSRI for Mr. B (who has never taken antidepressants), start with a low dose—such as fluoxetine, 10 mg/d, or sertraline, 25 mg/d—for several days. Because patients might not bring up suicidal thoughts or feelings, encourage openness and ask nonthreatening questions, such as, “Have you felt hopeless or had any thoughts that life isn’t worth it lately?” See Table 534 for other prescribing recommendations.

Suicide is the third leading cause of death in persons age 18 to 2411 and a risk inherent in depression. Recent meta-analyses and large clinic population studies of adolescents and young adults suggest antidepressants—particularly SSRIs—show efficacy for depression and anxiety disorders12 and reduce the risk of suicide attempts.25

Clinical Point

To encourage patients to keep follow-up appointments, don’t prescribe refills early in antidepressant treatment

When deciding whether to prescribe an SSRI to an adult, weigh the small possible elevated risk in patients age 18 to 24 against the risk of untreated depression. The increase in suicide rates in children and adolescents after antidepressant prescription rates dropped in 2004 is consistent with a net beneficial effect of antidepressants. As in all collaborative treatment discussions, provide patients with comprehensive information on depression treatment options so that they can make informed decisions.

Related Resources

Table 5

Clinical recommendations when starting young adults
on antidepressant therapy

Start with a low dosage (such as fluoxetine, 10 mg/d; sertraline, 25 mg/d; paroxetine, 5 mg/d; citalopram, 10 mg/d; or escitalopram, 5 mg/d) for several days
Schedule a follow-up appointment at the end of the initial consultation
Make weekly contact in person or by phone for the first weeks after starting an antidepressant
Don’t prescribe large quantities of medication that could provide means for an overdose, but not so little that the patient is likely to run out
Don’t provide refills early in treatment to encourage follow-up
Assess regularly for suicidal thoughts and common comorbidities such as hopelessness, substance abuse, and history of impulsive aggression
Document contacts with patient, risk/benefit discussions, information provided, and rationale for your assessment and plan
Consider augmenting pharmacotherapy with psychotherapy; evidence indicates combination treatment may be safer and more effective than either therapy alone34

Drug brand names

  • Bupropion • Wellbutrin
  • Citalopram • Celexa
  • Duloxetine • Cymbalta
  • Escitalopram • Lexapro
  • Fluoxetine • Prozac
  • Fluvoxamine • Luvox
  • Mirtazapine • Remeron
  • Nefazodone • Serzone
  • Paroxetine • Paxil
  • Sertraline • Zoloft
  • Venlafaxine • Efiexor

Disclosures

Dr. Grunebaum reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Mann receives research support from GlaxoSmithKline and Novartis.

Acknowledgement

Dr. Grunebaum’s research is supported by NARSAD (a not-for-profit mental health research association) and NIMH K23 MH076049; GlaxoSmithKline donated medication for his NIMH-funded clinical trial.

References

1. Kuehn BM. FDA panel seeks to balance risks in warnings for antidepressants. J Am Med Assoc 2007;297:573-4.

2. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States, 1985-1999. J Clin Psychiatry 2004;65(11):1456-62.

3. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-10.

4. King RA, Riddle MA, Chappell PB, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30(2):179-86.

5. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991;52:491-3.

6. Beasley CM, Dornseif BE, Bosomworth JC, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303:685-92.

7. Hammad TA. Review and evaluation of clinical data. Food and Drug Administration. August 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf. Accessed September 19, 2007.

8. Nemeroff CB, Kalali A, Keller MB, et al. Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States. Arch Gen Psychiatry 2007;64(4):466-72.

9. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164:1356-63.

10. Libby AM, Brent DA, Morrato EH, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007;164(6):884-91.

11. US. Department of Health and Human Services. Centers for Disease Control and Prevention. Fatal injury reports. Web-based injury statistics query and reporting system. Available at: http://www.cdc.gov/NCIPC/wisqars. Accessed July 16, 2007.

12. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96.

13. Levenson M, Holland C. Statistical evaluation of suicidality in adults treated with antidepressants. In: Laughren TP. Memorandum: overview for December 13 meeting of PsychopharmacologicDrugs Advisory Committee (PDAC). Center for Drug Evaluation and Research, US Food and Drug Administration. November 16, 2006. Available at: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Accessed October 11, 2007.

14. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry 2000;157(12):1925-32.

15. Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006;166(7):719-28.

16. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790-2.

17. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. J Am Med Assoc 2004;292(3):338-43.

18. 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(7488):389.-

19. 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(7488):385-9.

20. 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(7488):396.-

21. Juurlink DN, Mamdani MM, Kopp A, Redelmeier DA. The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry 2006;163(5):813-21.

22. Isacsson G, Holmgren P, Ahlner J. Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides. Acta Psychiatr Scand. 2005;111(4):286-90.

23. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163(1):41-7.

24. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry 2007;164(7):1044-9.

25. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry 2007;164(7):1029-34.

26. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

27. Rich CL, Isacsson G. Suicide and antidepressants in South Alabama: evidence for improved treatment of depression. J Affect Disord 1997;45:135-42.

28. Isacsson G, Bergman U, Rich CL. Antidepressants, depression and suicide: an analysis of the San Diego study. J Affect Disord 1994;32:277-86.

29. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003;361(9358):653-61.

30. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005;62(2):165-72.

31. Hall WD, Mant A, Mitchell PB, et al. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326(7397):1008-11.

32. Nakagawa A, Grunebaum MF, Ellis SP, et al. Association of suicide and antidepressant prescription rates in Japan, 1999-2003. J Clin Psychiatry 2007;68(6):908-16.

33. Helgason T, Tomasson H, Zoega T. Antidepressants and public health in Iceland. Time series analysis of national data. Br J Psychiatry 2004;184:157-62.

34. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004;292(7):807-20.

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CASE: Life is 'not worth it'

Mr. B, age 20, has taken a semester leave from college because of gradually worsening depressed mood. Over the past 2 months he has lost interest in jogging and playing piano—which he usually enjoys. He reports reduced libido, middle insomnia, loss of appetite, feeling as if his head is “full of cotton,” trouble concentrating, and waking in the morning with a sense of dread. His anxiety dissipates during the day, but he continues to feel sad and sometimes weepy, which is unusual for him.

Clinical Point

In 2003 to 2004, after the ‘black-box’ warning, pediatric antidepressant prescriptions declined and suicide rates increased 11%

Mr. B reports feeling hopeless at times and has had vague thoughts about life being “not worth it if I continue to feel like this” but denies specific suicide plans. Your initial impression is that Mr. B is in the midst of a major depressive episode and that a selective serotonin reuptake inhibitor (SSRI) is indicated. As you finish taking his history, you run through your mind the pros and cons of the recommendation you will make to him.

Do SSRIs raise or lower the risk for suicidal behavior in young adults such as Mr. B? The answer is complicated and goes beyond an “either/or” question, as the FDA acknowledged in May 2007 when it:

  • extended the black-box warning of increased suicidality risk with antidepressants to cover adults age 18 to 24 as well as children and adolescents
  • included language in the warning about the benefits of treating depression and the suicide risk associated with untreated depression, given concerns about declining antidepressant prescriptions and rising suicides among youth.1
  • To help you make informed decisions when treating depression in adults, this article reviews the studies leading up to and following the FDA’s meta-analysis of antidepressant trial data in patients age 18 and older. Our goal is to provide a framework for clinical treatment of adults age 18 to 24 and those age ≥25.

Box

FDA’s pediatric suicidality analysis: What the data showed

The FDA meta-analysis designed to investigate a reported association between antidepressants and suicidality in children and adolescents found contradictory results:

  • Pooled adverse event data from 24 pediatric antidepressant trials totaling >4,400 patients showed a higher risk of suicidal ideation or behavior (no suicides occurred) with antidepressants (4%) vs placebo (2%).
  • Systematically collected suicide-related item scores from 17 of the trials showed no evidence that antidepressants worsen suicidality or cause it to emerge.

One interpretation of these findings is that antidepressants’ effect on suicidality is small and therefore subject to measurement error.

Another is ascertainment bias; any side effect associated with active medication encourages discussion with the clinician and may distort the frequency of reported adverse events.

The FDA meta-analysis also found:

  • Relative risk for suicidality ranged 10-fold among agents, from 0.9 with fluoxetine to 8.8 with venlafaxine.
  • Most suicide-related events occurred in subjects having the highest baseline levels of suicidality.
  • Hostility and agitation emerged with SSRI use, particularly during the first month of treatment.
  • Patient age, sex, or history of suicide attempt/ideation did not affect the results.

Source: Reference 7

First hints of suicidality

SSRIs revolutionized depression treatment. From 1985 to 1999, annual U.S. antidepressant prescriptions quadrupled, with SSRIs accounting for 70% of the increase (see “Antidepressants and suicide risk, 1985 to 2007”). At the same time, the age-adjusted suicide rate:

Clinical Point

FDA’s meta-analysis of suicide risk in adults found 8 suicides in 372 antidepressant trials totalling nearly 100,000 persons

  • dropped 22.5% for women (who account for twice as many antidepressant prescriptions as men)
  • dropped 12.8% for men (without change in the rank order of suicide methods).2
For many patients, increased antidepressant use improved treatment of major depressive and other antidepressant-responsive disorders. In 1990, however, case reports suggested SSRIs might cause suicidal thoughts or behavior.3 Hypothesized mechanisms included increased aggression4 and akathisia.5 An FDA review found no proof, and a meta-analysis of data from 17 double-blind, randomized, controlled trials found no association between fluoxetine and suicidal thoughts or behavior.6

The debate rekindled in June 2003 when the British Committee on Safety of Medicines warned against using paroxetine or venlafaxine in children. After conducting its own meta-analysis, the FDA in 2004 ordered a black-box warning about suicidality and the use of antidepressants in children and adolescents ( Box ).7

After the pediatric ‘black box.’ Antidepressant prescriptions for children and adolescents declined in the years 2003 to 2004, as did diagnosis of pediatric depression.8-10 Antidepressant prescribing also showed signs of shifting from general practitioners to psychiatrists.8 At the same time, the suicide rate among youth age 11 In patients age >60, SSRI prescriptions continued to rise and suicide rates fell,9 a pattern of change consistent with antidepressants protecting against suicide.

 

 

An independent meta-analysis by Bridge et al12 examined the pediatric trial data used in the FDA meta-analysis plus 7 additional studies. Its findings differ in 2 important ways from those of the FDA review:

  • Antidepressants—including others besides fluoxetine—showed efficacy in treating anxiety disorders and depression in children and adolescents.
  • The frequency of suicide-related adverse events (no trial patients committed suicide) was approximately 3% on active medication—25% lower than the FDA estimated rate—and 2% on placebo, similar to the FDA estimate.
The number needed to treat (NNT)— number of patients who must be treated to get a therapeutic response that would not have happened with placebo—ranged from 3 to 10. The number needed to harm (NNH)—number of patients who must be treated for 1 suicidal ideation/nonfatal attempt to occur that would not have happened with placebo—ranged from 112 to 200. The authors interpreted this as “indicating a favorable overall risk-to-benefit profile for antidepressants in the treatment of pediatric [major depressive disorder], [obsessive-compulsive disorder] (OCD), and non-OCD anxiety disorders.”12 These findings appear to support the efficacy of antidepressants in pediatric patients and a favorable risk-benefit ratio.

Antidepressants and suicide risk, 1985 to 2007

19851990199119992003200420062007
 Case reports suggest link between suicide and SSRI useFDA analysis finds no association between SSRIs and increased suicide risk UK agency warns of suicide-related events in children treated with paroxetine and venlafaxineFDA conducts meta-analysis, requires black-box warnings of risk of suicidality in youth taking antidepressantsFDA meta-analysis finds age-dependent effect of antidepressants on suicidality risk in adultsFDA expands warning of increased suicidality risk with antidepressants to adults age
Antidepressant prescriptions quadruple; age-adjusted suicide rate drops 22.5% for women and 12.8% for menPediatric depression diagnoses and antidepressant prescriptions decline; suicides increase 11%Bridge et al meta-analysis finds 25% lower rate of suicide-related events in youth than the FDA found

What about adults?

Overall effect. A subsequent FDA meta-analysis of antidepressant clinical trial data in adults13 found 8 suicides in 372 trials totaling nearly 100,000 persons. All occurred in the 295 trials with psychiatric indications. Among these psychiatric trials, 59% had a suicidal behavior/ideation event in either the test-drug or placebo arm, and 41% had none. Eleven antidepressants were included in the meta-analysis:

Clinical Point

Antidepressants’ antisuicidality benefit appears greater for patients age ≥ 25 than for those age 18 to 24

  • 6 SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
  • 2 SNRIs (duloxetine and venlafaxine)
  • 3 others (bupropion, mirtazapine, and nefazodone).
Overall, antidepressants showed a protective (antisuicidal) effect in adults as compared with placebo (odds ratio 0.85 [95% CI: 0.71 to 1.02, P=0.08]), with no difference in effect between SSRIs and non-SSRIs.

Age-specific findings. When the FDA analysis was stratified by age, however, antidepressants’ benefit appeared greater for patients age ≥25 than for those age 18 to 24. The data suggested:

  • elevated suicidality risk among adults age
  • neutral or possibly protective effect for adults age 25 to 64
  • protective effect in adults age ≥65 ( Table 1 ).13
Table 1

FDA meta-analysis: Suicide rates by age in antidepressant trials

Age group (yr)Suicide rate (%)(test drug/placebo)Suicide attempt rate (%)(test drug/placebo)
18 to 240.03/0.000.55/0.27
25 to 300.00/0.030.23/0.11
31 to 640.01/0.000.13/0.15
≥650.00/0.040.03/0.25
Source: Reference 13
For 18-to 24-year-olds, the suicide rate was 0.03% (~1/4,000) in these mostly 8- to 12-week trials, and the suicide attempt rate was 0.55% (~1/200). For comparison, the lifetime prevalence of suicide was 2.2% to 8.6%—depending partly on illness severity—in a meta-analysis of patients with mood disorders.14

The odds ratio for suicidal behavior (preparatory acts, attempt, or suicide) for subacts, attempt, or suicide) for subjects age 18 to 24 on test drug vs placebo was 2.31 (95% CI: 1.02, 5.64) [event rate/sample: 23/3810 vs 8/2604]. NNH was 333, which means 333 adults in this age group would need to be treated with an antidepressant for 1 to experience a suicidal behavior event that would not have happened with placebo.

Clinical Point

Suicide attempt rates decline steadily after antidepressant or psychotherapy begins in depressed adults (including those age Compare an NNH of 333 with the much lower NNH values associated with antiarrhythmic treatment of atrial fibrillation (AF),15 an important cardiovascular cause of morbidity and mortality. A meta-analysis of 44 AF trials totalling 11,322 subjects found that—although “moderately effective” for maintaining sinus rhythm—all but 2 of the 10 drugs were pro-arrhythmic. Their NNH values of 17 to 119 are, at best, approximately one-third the NNH for antidepressants for suicidality in young adults based on adverse event reports. With NNH, higher is safer.

The age-related pattern the FDA found in its adult meta-analysis ( Table 2 )13 is consistent with its earlier pediatric analysis7 but not with the more recent findings of Bridge et al12 that included a larger data set.

Table 2

FDA meta-analysis: Risk of suicidality in adults taking antidepressants

Protective benefit appeared greater for dults age ≥25 than for those age 18 to 24
Elevated risk appeared to apply to adults age
A “slight suggestion” of increased risk was seen with SNRIs vs other classes, but no significant differences among drugs or drug classes
Risk was increased in adults who did not respond to active drug treatment
Risk was not affected by patient sex, race, geographic location, inpatient vs outpatient care, or treatment with SSRIs vs non-SSRIs
Risk may be lower with sertraline than with other antidepressants, although this trend could be a false-positive result related to multiple tests
A “sensitivity analysis” using alternate statistical methods to test the robustness of the findings yielded similar results
SNRIs: serotonin-norepinephrine reuptake inhibitors;
SSRIs: selective serotonin reuptake inhibitors
Source: Reference 13

Mixed evidence

Aside from the FDA meta-analysis,13 what is the evidence that antidepressants—or specifically SSRIs—may cause suicidality in adults? Among 9 major published studies in adults of the relationship between SSRIs and suicidal behavior (deaths or attempts):

Clinical Point

If you decide to prescribe an SSRI for a depressed young adult, start with a low dosage (such as fluoxetine, 10 mg/d) for several days

Table 3A

4 studies found no relationship
between SSRI use and suicide in adults

Study designMain resultsLimitations
Meta-analysis of FDA data by Khan et al;16 >48,000 patients in trials that included fluoxetine, sertraline, paroxetine, citalopramNo difference in suicide rates among SSRIs, other antidepressants, or placeboPatients not representative of general clinical population
Trials mostly short-term; tended to exclude suicidal patients
Case-control study in UK primary care practice by Jick et al;17 antidepressant users, 555 with suicidal behavior vs 2,062 withoutRisk of suicidal ideation or behavior did not differ between SSRIs vs non-SSRIsObservational study
Confounding by indication*
Case-control study in UK primary care practice by Martinez et al;18 >146,000 persons, first antidepressant prescription for depressionNo evidence that risk of suicide or nonfatal self-harm was greater with SSRIs than with tricyclicsObservational study
Confounding by indication*
Meta-analysis in UK by Gunnell et al;19 477 clinical trials (N>40,000) of SSRIs vs placebo in depressionNo evidence that SSRIs increased suicide risk
Weak evidence of increased self-harm risk		Lack of individual or trial-level data
Evidence suggests nonfatal suicidal ideation/self-harm events are underreported
SSRI: selective serotonin reuptake inhibitor; UK: United Kingdom
* Confounding by indication: Clinicians may preferentially prescribe SSRIs to patients thought to be at risk for suicide because of these drugs’ relative safety in overdose.

Table 3B

2 studies found SSRIs may increase suicide risk in adults

Study designMain resultsLimitations
Meta-analysis (1967 to 2003) by Fergusson et al;20 702 trials comparing SSRIs vs placebo or other drug for any condition (N>87,000)Suicide attempts almost twice as likely with SSRIs vs placebo, but no difference in fatal attempts; no difference in risk between SSRIs and TCAsMany methodologic limitations in clinical trials, such as underreporting of suicidal behavior
Limited to public data
Case-control study of geriatric population in Ontario by Juurlink et al;21 1,138 suicides vs 4,552 controls matched for demographic characteristics and antecedent illness patternsSSRIs were associated with higher risk of suicide than other antidepressants during first month of therapy (adjusted OR: 4.8, 95% CI=1.9–12.2)
Risk independent of recent diagnosis of depression or receipt of psychiatric care
Violent suicides more common with SSRIs than other antidepressants
No difference in suicide risk after first month
Absolute risk of suicide with antidepressants was low		Confounding by indication*
14% of suicide sample excluded from analysis
CI: confidence interval; OR: odds ratio; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; UK: United Kingdom
* Confounding by indication: Clinicians may preferentially prescribe SSRIs to patients thought to be at risk for suicide because of these drugs’ relative safety in overdose.

Table 3C

3 studies found SSRIs may lower suicide risk in adults

Study designMain resultsLimitations
Case-control forensic toxicology by Isacsson et al;22 14,857 suicides compared with 26,422 deaths by accident or natural causes in Sweden (1992 to 2000)SSRIs less likely than other antidepressants to be detected in suicide victimsNaturalistic study
Possible residual confounding
Observational study by Simon et al;23 82,285 antidepressant treatment episodes among 65,103 health plan outpatients (1992 to 2003)Suicide risk in acute-phase treatment ~1/3,000; risk of suicide attempt leading to hospitalization ~1/1,000
No increased risk of suicide or serious attempt suggested during first month of treatment
No greater risk seen with newer drugs (mostly SSRIs)
General decline in risk of suicide attempts after starting antidepressant treatment		Potential uncontrolled confounding
Geographically limited sample
Possible misclassification in computerized records
Lack of data on medication adherence
Death certificates may underestimate suicide rates
Observational study by Gibbons et al24 of suicide attempts in veterans treated for depression; 226,866 patients treated with SSRI, other antidepressant, or no antidepressant (2003 to 2004)SSRI treatment associated with ~1/3 lower risk of suicide attempts compared with no antidepressant treatment
Finding consistent in veterans age 18 to 25 and in older veterans		Sample of veterans, 92% male
Dataset did not include suicides, so results pertain only to suicide attempts
SSRIs: selective serotonin reuptake inhibitors

Evidence of protection

Epidemiologic studies. Suicide attempt rates in depressed youth and adults—including those age 25

Evidence from psychological autopsies—which attempt to reconstruct a decedent’s thoughts, feelings, and actions before death—indicates that:

  • Approximately 60% of suicides occur in persons with a mood disorder.26
  • Since the advent of SSRIs, the rate of postmortem detection of antidepressants in suicides has increased from 8% to 15%, whereas the rate of suicide deaths caused by antidepressant overdose remains at approximately 5%.27
Similarly, in 1 suicide study, no antidepressants were detected postmortem in >50% of persons for whom they had been prescribed.28 Systematic review finds substantial literature showing antidepressants’ efficacy for major depressive disorder.29

Population studies in the United States30 and many other31,32 —but not all33 —countries report a correlation between increased antidepressant prescriptions and lower suicide rates. Because of their limitations, however, population studies cannot make a causal connection between antidepressant prescribing and suicide rates.

Randomized, controlled trials (RCTs) reduce sources of bias, but designing an RCT to test whether or not antidepressants prevent suicide is not feasible. Given suicide’s relative infrequency (~11 per 100,000 persons/year in the United States11 ), an RCT would require a sample of many thousands.

Meta-analyses of data pooled from smaller trials—such as the FDA studies of antidepressants and suicidality7,13 —are done to gain statistical power from larger samples, but these also have methodologic limitations ( Table 4 ). Proxy outcomes— such as suicide attempts and ideation in high-risk samples—also can be studied, as we are doing in our clinic (see Related Resources ).

Table 4

SSRIs and suicidality:
Limitations of the FDA’s meta-analyses of pooled data

The pooled clinical trials were not designed to measure suicidality, so relevant data were not collected systematically
Suicidal patients who are most at risk tend to be excluded from industry-sponsored trials
Post hoc analyses of safety and effects on suicidality are subject to limitations of multiple testing and possible false-positives
The FDA “suicidality” outcome variable, which combined suicidal ideation and behavior, is subject to measurement bias. It was constructed after the trials were completed and relied on spontaneously reported adverse events (not systematic assessment). If subjects on active drug had more physical side effects, they might have had greater contact with their physicians and more opportunities to report suicidal ideation or behavior
The pooled trials were conducted over many years and study samples may have changed over time, with later studies enrolling more treatment-resistant subjects

CASE CONTINUED: Hypomanic, or just in love?

Clinical Point

Make weekly contact with the patient by phone or in person for the first few weeks after starting SSRI treatment

Mr. B reports no medical problems and is taking no medications. He talked to a college counselor 3 times during his freshman year when he was upset after a romantic breakup, found it helpful, and says his feelings resolved. He reports trying marijuana and cocaine “a few times.” During his sophomore year he felt very happy and energized about a new relationship for approximately 1 week, but says he was sleeping normally and functioning well in school during that time.

He describes his father as very “serious” and sometimes pessimistic, but he does not know if his father ever had mental health treatment. On mental status exam, Mr. B is neat, cooperative, and looks worried. His speech is slightly labored and ruminative. His psychomotor state is normal. He has no psychotic symptoms, and his cognitive exam is normal. Because he is out of school, he has no health insurance.

Clinical recommendations

Case presentations such as Mr. B’s raise questions you must consider when prescribing SSRIs, particularly to young adults:

Clinical Point

When prescribing SSRIs, assess the patient regularly for suicidal thoughts, hopelessness, substance abuse, and impulsivity

  • Was his “energized” episode a mild hypomanic period or just normal feelings of “being in love”?
  • Is he minimizing substance use, which is a common comorbidity in depressed persons who die by suicide?
  • He has melancholic symptoms; does he have psychotic ruminations he is not sharing?
  • Without health insurance, how frequently will he be able to make follow-up appointments?

Prescribing any antidepressant for a specific patient is a complex, individualized decision based on weighing risks vs benefits. If you decide to prescribe an SSRI for Mr. B (who has never taken antidepressants), start with a low dose—such as fluoxetine, 10 mg/d, or sertraline, 25 mg/d—for several days. Because patients might not bring up suicidal thoughts or feelings, encourage openness and ask nonthreatening questions, such as, “Have you felt hopeless or had any thoughts that life isn’t worth it lately?” See Table 534 for other prescribing recommendations.

Suicide is the third leading cause of death in persons age 18 to 2411 and a risk inherent in depression. Recent meta-analyses and large clinic population studies of adolescents and young adults suggest antidepressants—particularly SSRIs—show efficacy for depression and anxiety disorders12 and reduce the risk of suicide attempts.25

Clinical Point

To encourage patients to keep follow-up appointments, don’t prescribe refills early in antidepressant treatment

When deciding whether to prescribe an SSRI to an adult, weigh the small possible elevated risk in patients age 18 to 24 against the risk of untreated depression. The increase in suicide rates in children and adolescents after antidepressant prescription rates dropped in 2004 is consistent with a net beneficial effect of antidepressants. As in all collaborative treatment discussions, provide patients with comprehensive information on depression treatment options so that they can make informed decisions.

Related Resources

Table 5

Clinical recommendations when starting young adults
on antidepressant therapy

Start with a low dosage (such as fluoxetine, 10 mg/d; sertraline, 25 mg/d; paroxetine, 5 mg/d; citalopram, 10 mg/d; or escitalopram, 5 mg/d) for several days
Schedule a follow-up appointment at the end of the initial consultation
Make weekly contact in person or by phone for the first weeks after starting an antidepressant
Don’t prescribe large quantities of medication that could provide means for an overdose, but not so little that the patient is likely to run out
Don’t provide refills early in treatment to encourage follow-up
Assess regularly for suicidal thoughts and common comorbidities such as hopelessness, substance abuse, and history of impulsive aggression
Document contacts with patient, risk/benefit discussions, information provided, and rationale for your assessment and plan
Consider augmenting pharmacotherapy with psychotherapy; evidence indicates combination treatment may be safer and more effective than either therapy alone34

Drug brand names

  • Bupropion • Wellbutrin
  • Citalopram • Celexa
  • Duloxetine • Cymbalta
  • Escitalopram • Lexapro
  • Fluoxetine • Prozac
  • Fluvoxamine • Luvox
  • Mirtazapine • Remeron
  • Nefazodone • Serzone
  • Paroxetine • Paxil
  • Sertraline • Zoloft
  • Venlafaxine • Efiexor

Disclosures

Dr. Grunebaum reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Mann receives research support from GlaxoSmithKline and Novartis.

Acknowledgement

Dr. Grunebaum’s research is supported by NARSAD (a not-for-profit mental health research association) and NIMH K23 MH076049; GlaxoSmithKline donated medication for his NIMH-funded clinical trial.

CASE: Life is 'not worth it'

Mr. B, age 20, has taken a semester leave from college because of gradually worsening depressed mood. Over the past 2 months he has lost interest in jogging and playing piano—which he usually enjoys. He reports reduced libido, middle insomnia, loss of appetite, feeling as if his head is “full of cotton,” trouble concentrating, and waking in the morning with a sense of dread. His anxiety dissipates during the day, but he continues to feel sad and sometimes weepy, which is unusual for him.

Clinical Point

In 2003 to 2004, after the ‘black-box’ warning, pediatric antidepressant prescriptions declined and suicide rates increased 11%

Mr. B reports feeling hopeless at times and has had vague thoughts about life being “not worth it if I continue to feel like this” but denies specific suicide plans. Your initial impression is that Mr. B is in the midst of a major depressive episode and that a selective serotonin reuptake inhibitor (SSRI) is indicated. As you finish taking his history, you run through your mind the pros and cons of the recommendation you will make to him.

Do SSRIs raise or lower the risk for suicidal behavior in young adults such as Mr. B? The answer is complicated and goes beyond an “either/or” question, as the FDA acknowledged in May 2007 when it:

  • extended the black-box warning of increased suicidality risk with antidepressants to cover adults age 18 to 24 as well as children and adolescents
  • included language in the warning about the benefits of treating depression and the suicide risk associated with untreated depression, given concerns about declining antidepressant prescriptions and rising suicides among youth.1
  • To help you make informed decisions when treating depression in adults, this article reviews the studies leading up to and following the FDA’s meta-analysis of antidepressant trial data in patients age 18 and older. Our goal is to provide a framework for clinical treatment of adults age 18 to 24 and those age ≥25.

Box

FDA’s pediatric suicidality analysis: What the data showed

The FDA meta-analysis designed to investigate a reported association between antidepressants and suicidality in children and adolescents found contradictory results:

  • Pooled adverse event data from 24 pediatric antidepressant trials totaling >4,400 patients showed a higher risk of suicidal ideation or behavior (no suicides occurred) with antidepressants (4%) vs placebo (2%).
  • Systematically collected suicide-related item scores from 17 of the trials showed no evidence that antidepressants worsen suicidality or cause it to emerge.

One interpretation of these findings is that antidepressants’ effect on suicidality is small and therefore subject to measurement error.

Another is ascertainment bias; any side effect associated with active medication encourages discussion with the clinician and may distort the frequency of reported adverse events.

The FDA meta-analysis also found:

  • Relative risk for suicidality ranged 10-fold among agents, from 0.9 with fluoxetine to 8.8 with venlafaxine.
  • Most suicide-related events occurred in subjects having the highest baseline levels of suicidality.
  • Hostility and agitation emerged with SSRI use, particularly during the first month of treatment.
  • Patient age, sex, or history of suicide attempt/ideation did not affect the results.

Source: Reference 7

First hints of suicidality

SSRIs revolutionized depression treatment. From 1985 to 1999, annual U.S. antidepressant prescriptions quadrupled, with SSRIs accounting for 70% of the increase (see “Antidepressants and suicide risk, 1985 to 2007”). At the same time, the age-adjusted suicide rate:

Clinical Point

FDA’s meta-analysis of suicide risk in adults found 8 suicides in 372 antidepressant trials totalling nearly 100,000 persons

  • dropped 22.5% for women (who account for twice as many antidepressant prescriptions as men)
  • dropped 12.8% for men (without change in the rank order of suicide methods).2
For many patients, increased antidepressant use improved treatment of major depressive and other antidepressant-responsive disorders. In 1990, however, case reports suggested SSRIs might cause suicidal thoughts or behavior.3 Hypothesized mechanisms included increased aggression4 and akathisia.5 An FDA review found no proof, and a meta-analysis of data from 17 double-blind, randomized, controlled trials found no association between fluoxetine and suicidal thoughts or behavior.6

The debate rekindled in June 2003 when the British Committee on Safety of Medicines warned against using paroxetine or venlafaxine in children. After conducting its own meta-analysis, the FDA in 2004 ordered a black-box warning about suicidality and the use of antidepressants in children and adolescents ( Box ).7

After the pediatric ‘black box.’ Antidepressant prescriptions for children and adolescents declined in the years 2003 to 2004, as did diagnosis of pediatric depression.8-10 Antidepressant prescribing also showed signs of shifting from general practitioners to psychiatrists.8 At the same time, the suicide rate among youth age 11 In patients age >60, SSRI prescriptions continued to rise and suicide rates fell,9 a pattern of change consistent with antidepressants protecting against suicide.

 

 

An independent meta-analysis by Bridge et al12 examined the pediatric trial data used in the FDA meta-analysis plus 7 additional studies. Its findings differ in 2 important ways from those of the FDA review:

  • Antidepressants—including others besides fluoxetine—showed efficacy in treating anxiety disorders and depression in children and adolescents.
  • The frequency of suicide-related adverse events (no trial patients committed suicide) was approximately 3% on active medication—25% lower than the FDA estimated rate—and 2% on placebo, similar to the FDA estimate.
The number needed to treat (NNT)— number of patients who must be treated to get a therapeutic response that would not have happened with placebo—ranged from 3 to 10. The number needed to harm (NNH)—number of patients who must be treated for 1 suicidal ideation/nonfatal attempt to occur that would not have happened with placebo—ranged from 112 to 200. The authors interpreted this as “indicating a favorable overall risk-to-benefit profile for antidepressants in the treatment of pediatric [major depressive disorder], [obsessive-compulsive disorder] (OCD), and non-OCD anxiety disorders.”12 These findings appear to support the efficacy of antidepressants in pediatric patients and a favorable risk-benefit ratio.

Antidepressants and suicide risk, 1985 to 2007

19851990199119992003200420062007
 Case reports suggest link between suicide and SSRI useFDA analysis finds no association between SSRIs and increased suicide risk UK agency warns of suicide-related events in children treated with paroxetine and venlafaxineFDA conducts meta-analysis, requires black-box warnings of risk of suicidality in youth taking antidepressantsFDA meta-analysis finds age-dependent effect of antidepressants on suicidality risk in adultsFDA expands warning of increased suicidality risk with antidepressants to adults age
Antidepressant prescriptions quadruple; age-adjusted suicide rate drops 22.5% for women and 12.8% for menPediatric depression diagnoses and antidepressant prescriptions decline; suicides increase 11%Bridge et al meta-analysis finds 25% lower rate of suicide-related events in youth than the FDA found

What about adults?

Overall effect. A subsequent FDA meta-analysis of antidepressant clinical trial data in adults13 found 8 suicides in 372 trials totaling nearly 100,000 persons. All occurred in the 295 trials with psychiatric indications. Among these psychiatric trials, 59% had a suicidal behavior/ideation event in either the test-drug or placebo arm, and 41% had none. Eleven antidepressants were included in the meta-analysis:

Clinical Point

Antidepressants’ antisuicidality benefit appears greater for patients age ≥ 25 than for those age 18 to 24

  • 6 SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
  • 2 SNRIs (duloxetine and venlafaxine)
  • 3 others (bupropion, mirtazapine, and nefazodone).
Overall, antidepressants showed a protective (antisuicidal) effect in adults as compared with placebo (odds ratio 0.85 [95% CI: 0.71 to 1.02, P=0.08]), with no difference in effect between SSRIs and non-SSRIs.

Age-specific findings. When the FDA analysis was stratified by age, however, antidepressants’ benefit appeared greater for patients age ≥25 than for those age 18 to 24. The data suggested:

  • elevated suicidality risk among adults age
  • neutral or possibly protective effect for adults age 25 to 64
  • protective effect in adults age ≥65 ( Table 1 ).13
Table 1

FDA meta-analysis: Suicide rates by age in antidepressant trials

Age group (yr)Suicide rate (%)(test drug/placebo)Suicide attempt rate (%)(test drug/placebo)
18 to 240.03/0.000.55/0.27
25 to 300.00/0.030.23/0.11
31 to 640.01/0.000.13/0.15
≥650.00/0.040.03/0.25
Source: Reference 13
For 18-to 24-year-olds, the suicide rate was 0.03% (~1/4,000) in these mostly 8- to 12-week trials, and the suicide attempt rate was 0.55% (~1/200). For comparison, the lifetime prevalence of suicide was 2.2% to 8.6%—depending partly on illness severity—in a meta-analysis of patients with mood disorders.14

The odds ratio for suicidal behavior (preparatory acts, attempt, or suicide) for subacts, attempt, or suicide) for subjects age 18 to 24 on test drug vs placebo was 2.31 (95% CI: 1.02, 5.64) [event rate/sample: 23/3810 vs 8/2604]. NNH was 333, which means 333 adults in this age group would need to be treated with an antidepressant for 1 to experience a suicidal behavior event that would not have happened with placebo.

Clinical Point

Suicide attempt rates decline steadily after antidepressant or psychotherapy begins in depressed adults (including those age Compare an NNH of 333 with the much lower NNH values associated with antiarrhythmic treatment of atrial fibrillation (AF),15 an important cardiovascular cause of morbidity and mortality. A meta-analysis of 44 AF trials totalling 11,322 subjects found that—although “moderately effective” for maintaining sinus rhythm—all but 2 of the 10 drugs were pro-arrhythmic. Their NNH values of 17 to 119 are, at best, approximately one-third the NNH for antidepressants for suicidality in young adults based on adverse event reports. With NNH, higher is safer.

The age-related pattern the FDA found in its adult meta-analysis ( Table 2 )13 is consistent with its earlier pediatric analysis7 but not with the more recent findings of Bridge et al12 that included a larger data set.

Table 2

FDA meta-analysis: Risk of suicidality in adults taking antidepressants

Protective benefit appeared greater for dults age ≥25 than for those age 18 to 24
Elevated risk appeared to apply to adults age
A “slight suggestion” of increased risk was seen with SNRIs vs other classes, but no significant differences among drugs or drug classes
Risk was increased in adults who did not respond to active drug treatment
Risk was not affected by patient sex, race, geographic location, inpatient vs outpatient care, or treatment with SSRIs vs non-SSRIs
Risk may be lower with sertraline than with other antidepressants, although this trend could be a false-positive result related to multiple tests
A “sensitivity analysis” using alternate statistical methods to test the robustness of the findings yielded similar results
SNRIs: serotonin-norepinephrine reuptake inhibitors;
SSRIs: selective serotonin reuptake inhibitors
Source: Reference 13

Mixed evidence

Aside from the FDA meta-analysis,13 what is the evidence that antidepressants—or specifically SSRIs—may cause suicidality in adults? Among 9 major published studies in adults of the relationship between SSRIs and suicidal behavior (deaths or attempts):

Clinical Point

If you decide to prescribe an SSRI for a depressed young adult, start with a low dosage (such as fluoxetine, 10 mg/d) for several days

Table 3A

4 studies found no relationship
between SSRI use and suicide in adults

Study designMain resultsLimitations
Meta-analysis of FDA data by Khan et al;16 >48,000 patients in trials that included fluoxetine, sertraline, paroxetine, citalopramNo difference in suicide rates among SSRIs, other antidepressants, or placeboPatients not representative of general clinical population
Trials mostly short-term; tended to exclude suicidal patients
Case-control study in UK primary care practice by Jick et al;17 antidepressant users, 555 with suicidal behavior vs 2,062 withoutRisk of suicidal ideation or behavior did not differ between SSRIs vs non-SSRIsObservational study
Confounding by indication*
Case-control study in UK primary care practice by Martinez et al;18 >146,000 persons, first antidepressant prescription for depressionNo evidence that risk of suicide or nonfatal self-harm was greater with SSRIs than with tricyclicsObservational study
Confounding by indication*
Meta-analysis in UK by Gunnell et al;19 477 clinical trials (N>40,000) of SSRIs vs placebo in depressionNo evidence that SSRIs increased suicide risk
Weak evidence of increased self-harm risk		Lack of individual or trial-level data
Evidence suggests nonfatal suicidal ideation/self-harm events are underreported
SSRI: selective serotonin reuptake inhibitor; UK: United Kingdom
* Confounding by indication: Clinicians may preferentially prescribe SSRIs to patients thought to be at risk for suicide because of these drugs’ relative safety in overdose.

Table 3B

2 studies found SSRIs may increase suicide risk in adults

Study designMain resultsLimitations
Meta-analysis (1967 to 2003) by Fergusson et al;20 702 trials comparing SSRIs vs placebo or other drug for any condition (N>87,000)Suicide attempts almost twice as likely with SSRIs vs placebo, but no difference in fatal attempts; no difference in risk between SSRIs and TCAsMany methodologic limitations in clinical trials, such as underreporting of suicidal behavior
Limited to public data
Case-control study of geriatric population in Ontario by Juurlink et al;21 1,138 suicides vs 4,552 controls matched for demographic characteristics and antecedent illness patternsSSRIs were associated with higher risk of suicide than other antidepressants during first month of therapy (adjusted OR: 4.8, 95% CI=1.9–12.2)
Risk independent of recent diagnosis of depression or receipt of psychiatric care
Violent suicides more common with SSRIs than other antidepressants
No difference in suicide risk after first month
Absolute risk of suicide with antidepressants was low		Confounding by indication*
14% of suicide sample excluded from analysis
CI: confidence interval; OR: odds ratio; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; UK: United Kingdom
* Confounding by indication: Clinicians may preferentially prescribe SSRIs to patients thought to be at risk for suicide because of these drugs’ relative safety in overdose.

Table 3C

3 studies found SSRIs may lower suicide risk in adults

Study designMain resultsLimitations
Case-control forensic toxicology by Isacsson et al;22 14,857 suicides compared with 26,422 deaths by accident or natural causes in Sweden (1992 to 2000)SSRIs less likely than other antidepressants to be detected in suicide victimsNaturalistic study
Possible residual confounding
Observational study by Simon et al;23 82,285 antidepressant treatment episodes among 65,103 health plan outpatients (1992 to 2003)Suicide risk in acute-phase treatment ~1/3,000; risk of suicide attempt leading to hospitalization ~1/1,000
No increased risk of suicide or serious attempt suggested during first month of treatment
No greater risk seen with newer drugs (mostly SSRIs)
General decline in risk of suicide attempts after starting antidepressant treatment		Potential uncontrolled confounding
Geographically limited sample
Possible misclassification in computerized records
Lack of data on medication adherence
Death certificates may underestimate suicide rates
Observational study by Gibbons et al24 of suicide attempts in veterans treated for depression; 226,866 patients treated with SSRI, other antidepressant, or no antidepressant (2003 to 2004)SSRI treatment associated with ~1/3 lower risk of suicide attempts compared with no antidepressant treatment
Finding consistent in veterans age 18 to 25 and in older veterans		Sample of veterans, 92% male
Dataset did not include suicides, so results pertain only to suicide attempts
SSRIs: selective serotonin reuptake inhibitors

Evidence of protection

Epidemiologic studies. Suicide attempt rates in depressed youth and adults—including those age 25

Evidence from psychological autopsies—which attempt to reconstruct a decedent’s thoughts, feelings, and actions before death—indicates that:

  • Approximately 60% of suicides occur in persons with a mood disorder.26
  • Since the advent of SSRIs, the rate of postmortem detection of antidepressants in suicides has increased from 8% to 15%, whereas the rate of suicide deaths caused by antidepressant overdose remains at approximately 5%.27
Similarly, in 1 suicide study, no antidepressants were detected postmortem in >50% of persons for whom they had been prescribed.28 Systematic review finds substantial literature showing antidepressants’ efficacy for major depressive disorder.29

Population studies in the United States30 and many other31,32 —but not all33 —countries report a correlation between increased antidepressant prescriptions and lower suicide rates. Because of their limitations, however, population studies cannot make a causal connection between antidepressant prescribing and suicide rates.

Randomized, controlled trials (RCTs) reduce sources of bias, but designing an RCT to test whether or not antidepressants prevent suicide is not feasible. Given suicide’s relative infrequency (~11 per 100,000 persons/year in the United States11 ), an RCT would require a sample of many thousands.

Meta-analyses of data pooled from smaller trials—such as the FDA studies of antidepressants and suicidality7,13 —are done to gain statistical power from larger samples, but these also have methodologic limitations ( Table 4 ). Proxy outcomes— such as suicide attempts and ideation in high-risk samples—also can be studied, as we are doing in our clinic (see Related Resources ).

Table 4

SSRIs and suicidality:
Limitations of the FDA’s meta-analyses of pooled data

The pooled clinical trials were not designed to measure suicidality, so relevant data were not collected systematically
Suicidal patients who are most at risk tend to be excluded from industry-sponsored trials
Post hoc analyses of safety and effects on suicidality are subject to limitations of multiple testing and possible false-positives
The FDA “suicidality” outcome variable, which combined suicidal ideation and behavior, is subject to measurement bias. It was constructed after the trials were completed and relied on spontaneously reported adverse events (not systematic assessment). If subjects on active drug had more physical side effects, they might have had greater contact with their physicians and more opportunities to report suicidal ideation or behavior
The pooled trials were conducted over many years and study samples may have changed over time, with later studies enrolling more treatment-resistant subjects

CASE CONTINUED: Hypomanic, or just in love?

Clinical Point

Make weekly contact with the patient by phone or in person for the first few weeks after starting SSRI treatment

Mr. B reports no medical problems and is taking no medications. He talked to a college counselor 3 times during his freshman year when he was upset after a romantic breakup, found it helpful, and says his feelings resolved. He reports trying marijuana and cocaine “a few times.” During his sophomore year he felt very happy and energized about a new relationship for approximately 1 week, but says he was sleeping normally and functioning well in school during that time.

He describes his father as very “serious” and sometimes pessimistic, but he does not know if his father ever had mental health treatment. On mental status exam, Mr. B is neat, cooperative, and looks worried. His speech is slightly labored and ruminative. His psychomotor state is normal. He has no psychotic symptoms, and his cognitive exam is normal. Because he is out of school, he has no health insurance.

Clinical recommendations

Case presentations such as Mr. B’s raise questions you must consider when prescribing SSRIs, particularly to young adults:

Clinical Point

When prescribing SSRIs, assess the patient regularly for suicidal thoughts, hopelessness, substance abuse, and impulsivity

  • Was his “energized” episode a mild hypomanic period or just normal feelings of “being in love”?
  • Is he minimizing substance use, which is a common comorbidity in depressed persons who die by suicide?
  • He has melancholic symptoms; does he have psychotic ruminations he is not sharing?
  • Without health insurance, how frequently will he be able to make follow-up appointments?

Prescribing any antidepressant for a specific patient is a complex, individualized decision based on weighing risks vs benefits. If you decide to prescribe an SSRI for Mr. B (who has never taken antidepressants), start with a low dose—such as fluoxetine, 10 mg/d, or sertraline, 25 mg/d—for several days. Because patients might not bring up suicidal thoughts or feelings, encourage openness and ask nonthreatening questions, such as, “Have you felt hopeless or had any thoughts that life isn’t worth it lately?” See Table 534 for other prescribing recommendations.

Suicide is the third leading cause of death in persons age 18 to 2411 and a risk inherent in depression. Recent meta-analyses and large clinic population studies of adolescents and young adults suggest antidepressants—particularly SSRIs—show efficacy for depression and anxiety disorders12 and reduce the risk of suicide attempts.25

Clinical Point

To encourage patients to keep follow-up appointments, don’t prescribe refills early in antidepressant treatment

When deciding whether to prescribe an SSRI to an adult, weigh the small possible elevated risk in patients age 18 to 24 against the risk of untreated depression. The increase in suicide rates in children and adolescents after antidepressant prescription rates dropped in 2004 is consistent with a net beneficial effect of antidepressants. As in all collaborative treatment discussions, provide patients with comprehensive information on depression treatment options so that they can make informed decisions.

Related Resources

Table 5

Clinical recommendations when starting young adults
on antidepressant therapy

Start with a low dosage (such as fluoxetine, 10 mg/d; sertraline, 25 mg/d; paroxetine, 5 mg/d; citalopram, 10 mg/d; or escitalopram, 5 mg/d) for several days
Schedule a follow-up appointment at the end of the initial consultation
Make weekly contact in person or by phone for the first weeks after starting an antidepressant
Don’t prescribe large quantities of medication that could provide means for an overdose, but not so little that the patient is likely to run out
Don’t provide refills early in treatment to encourage follow-up
Assess regularly for suicidal thoughts and common comorbidities such as hopelessness, substance abuse, and history of impulsive aggression
Document contacts with patient, risk/benefit discussions, information provided, and rationale for your assessment and plan
Consider augmenting pharmacotherapy with psychotherapy; evidence indicates combination treatment may be safer and more effective than either therapy alone34

Drug brand names

  • Bupropion • Wellbutrin
  • Citalopram • Celexa
  • Duloxetine • Cymbalta
  • Escitalopram • Lexapro
  • Fluoxetine • Prozac
  • Fluvoxamine • Luvox
  • Mirtazapine • Remeron
  • Nefazodone • Serzone
  • Paroxetine • Paxil
  • Sertraline • Zoloft
  • Venlafaxine • Efiexor

Disclosures

Dr. Grunebaum reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Mann receives research support from GlaxoSmithKline and Novartis.

Acknowledgement

Dr. Grunebaum’s research is supported by NARSAD (a not-for-profit mental health research association) and NIMH K23 MH076049; GlaxoSmithKline donated medication for his NIMH-funded clinical trial.

References

1. Kuehn BM. FDA panel seeks to balance risks in warnings for antidepressants. J Am Med Assoc 2007;297:573-4.

2. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States, 1985-1999. J Clin Psychiatry 2004;65(11):1456-62.

3. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-10.

4. King RA, Riddle MA, Chappell PB, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30(2):179-86.

5. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991;52:491-3.

6. Beasley CM, Dornseif BE, Bosomworth JC, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303:685-92.

7. Hammad TA. Review and evaluation of clinical data. Food and Drug Administration. August 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf. Accessed September 19, 2007.

8. Nemeroff CB, Kalali A, Keller MB, et al. Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States. Arch Gen Psychiatry 2007;64(4):466-72.

9. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164:1356-63.

10. Libby AM, Brent DA, Morrato EH, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007;164(6):884-91.

11. US. Department of Health and Human Services. Centers for Disease Control and Prevention. Fatal injury reports. Web-based injury statistics query and reporting system. Available at: http://www.cdc.gov/NCIPC/wisqars. Accessed July 16, 2007.

12. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96.

13. Levenson M, Holland C. Statistical evaluation of suicidality in adults treated with antidepressants. In: Laughren TP. Memorandum: overview for December 13 meeting of PsychopharmacologicDrugs Advisory Committee (PDAC). Center for Drug Evaluation and Research, US Food and Drug Administration. November 16, 2006. Available at: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Accessed October 11, 2007.

14. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry 2000;157(12):1925-32.

15. Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006;166(7):719-28.

16. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790-2.

17. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. J Am Med Assoc 2004;292(3):338-43.

18. 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(7488):389.-

19. 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(7488):385-9.

20. 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(7488):396.-

21. Juurlink DN, Mamdani MM, Kopp A, Redelmeier DA. The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry 2006;163(5):813-21.

22. Isacsson G, Holmgren P, Ahlner J. Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides. Acta Psychiatr Scand. 2005;111(4):286-90.

23. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163(1):41-7.

24. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry 2007;164(7):1044-9.

25. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry 2007;164(7):1029-34.

26. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

27. Rich CL, Isacsson G. Suicide and antidepressants in South Alabama: evidence for improved treatment of depression. J Affect Disord 1997;45:135-42.

28. Isacsson G, Bergman U, Rich CL. Antidepressants, depression and suicide: an analysis of the San Diego study. J Affect Disord 1994;32:277-86.

29. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003;361(9358):653-61.

30. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005;62(2):165-72.

31. Hall WD, Mant A, Mitchell PB, et al. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326(7397):1008-11.

32. Nakagawa A, Grunebaum MF, Ellis SP, et al. Association of suicide and antidepressant prescription rates in Japan, 1999-2003. J Clin Psychiatry 2007;68(6):908-16.

33. Helgason T, Tomasson H, Zoega T. Antidepressants and public health in Iceland. Time series analysis of national data. Br J Psychiatry 2004;184:157-62.

34. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004;292(7):807-20.

References

1. Kuehn BM. FDA panel seeks to balance risks in warnings for antidepressants. J Am Med Assoc 2007;297:573-4.

2. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States, 1985-1999. J Clin Psychiatry 2004;65(11):1456-62.

3. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-10.

4. King RA, Riddle MA, Chappell PB, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30(2):179-86.

5. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991;52:491-3.

6. Beasley CM, Dornseif BE, Bosomworth JC, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303:685-92.

7. Hammad TA. Review and evaluation of clinical data. Food and Drug Administration. August 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf. Accessed September 19, 2007.

8. Nemeroff CB, Kalali A, Keller MB, et al. Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States. Arch Gen Psychiatry 2007;64(4):466-72.

9. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164:1356-63.

10. Libby AM, Brent DA, Morrato EH, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007;164(6):884-91.

11. US. Department of Health and Human Services. Centers for Disease Control and Prevention. Fatal injury reports. Web-based injury statistics query and reporting system. Available at: http://www.cdc.gov/NCIPC/wisqars. Accessed July 16, 2007.

12. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96.

13. Levenson M, Holland C. Statistical evaluation of suicidality in adults treated with antidepressants. In: Laughren TP. Memorandum: overview for December 13 meeting of PsychopharmacologicDrugs Advisory Committee (PDAC). Center for Drug Evaluation and Research, US Food and Drug Administration. November 16, 2006. Available at: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Accessed October 11, 2007.

14. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry 2000;157(12):1925-32.

15. Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006;166(7):719-28.

16. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790-2.

17. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. J Am Med Assoc 2004;292(3):338-43.

18. 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(7488):389.-

19. 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(7488):385-9.

20. 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(7488):396.-

21. Juurlink DN, Mamdani MM, Kopp A, Redelmeier DA. The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry 2006;163(5):813-21.

22. Isacsson G, Holmgren P, Ahlner J. Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides. Acta Psychiatr Scand. 2005;111(4):286-90.

23. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163(1):41-7.

24. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry 2007;164(7):1044-9.

25. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry 2007;164(7):1029-34.

26. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

27. Rich CL, Isacsson G. Suicide and antidepressants in South Alabama: evidence for improved treatment of depression. J Affect Disord 1997;45:135-42.

28. Isacsson G, Bergman U, Rich CL. Antidepressants, depression and suicide: an analysis of the San Diego study. J Affect Disord 1994;32:277-86.

29. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet 2003;361(9358):653-61.

30. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005;62(2):165-72.

31. Hall WD, Mant A, Mitchell PB, et al. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326(7397):1008-11.

32. Nakagawa A, Grunebaum MF, Ellis SP, et al. Association of suicide and antidepressant prescription rates in Japan, 1999-2003. J Clin Psychiatry 2007;68(6):908-16.

33. Helgason T, Tomasson H, Zoega T. Antidepressants and public health in Iceland. Time series analysis of national data. Br J Psychiatry 2004;184:157-62.

34. March J, Silva S, Petrycki S, et al. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA 2004;292(7):807-20.

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