Reexamining the suicide connection

The FDA issued a “black-box” warning for antidepressant labeling in 2004 because of concerns about a possible link between suicide and antidepressants in patients younger than age 18. Close to two years later, some community mental health providers say that family members’ and patients’ attitudes toward antidepressants have been affected by the FDA's move, but new research suggests the connection between antidepressant use and increased suicidality is not as strong as the FDA suspected—if it exists at all.

Karen Rhea, MD
“Psychiatrists and nurse practitioners at our organization believe that the black-box warning and the additional focus with parents on risk potential have decreased parental acceptance of these medications,” says Karen Rhea, MD, a child and adolescent psychiatrist and vice-president for medical services for Centerstone, a large community mental health provider organization in Tennessee.

Alexander Fariborzian, MD, medical director of Meridian Behavioral Healthcare in Gainesville, Florida, which serves 11 counties in North Florida, says the organization began issuing “advisories” to parents after the black-box warning went into effect. “Parents are provided with a copy of the advisory, and they are educated on new information in the black-box warning,” says Dr. Fariborzian. “Then they have to sign the advisory” to show consent for their child to receive medication, he says.

New Study Findings

Yet a new, large study indicates that the risk of suicide is decreased significantly in patients taking antidepressants.1Investigators assessed 82,285 treatment episodes in more than 65,000 adult and pediatric patients ranging in age from 5 to 105 who filled prescriptions for antidepressants while enrolled in a large health plan from 1992 to 2003. The mean age of the subjects was 44, and 5,107 episodes (6.2%) were among patients younger than age 18.

The researchers evaluated ten newer antidepressants, such as SSRIs and bupropion (Wellbutrin), and compared them with older antidepressants, such as tricyclics and trazodone. In a month-by-month analysis of newer antidepressants, suicide attempt rates were highest in the month before starting treatment, and risk during the first month of treatment was not significantly higher than in months two through six. Among patients on older drugs, the risk was highest during the first month of treatment, and that risk was significantly higher than in months two through six.

The risk of a suicide attempt was slightly higher in youths than in adults on antidepressant therapy (314 per 100,000 versus 78 per 100,000, respectively), but the study's lead author, Gregory Simon, MD, MPH, psychiatrist and researcher at the Group Health Cooperative in Seattle, says that suicide attempts among adolescents tend to be intrinsically higher than among adults. In addition, the risk of death by suicide was not significantly higher among adults and adolescents during the month after starting medication than during subsequent months.

“Our finding that suicide risk goes down after starting medication is true in adolescents, as well as adults,” Dr. Simon notes. “Our study shows that the risk of serious suicide attempt or suicide death after starting antidepressants is, fortunately, low. Contrary to conventional wisdom, the period after starting medication is not an especially high-risk period. In fact, risk goes down after starting medication.”

Different Views

The black-box warning on antidepressant product labeling, however, states that “antidepressants increase the risk of suicidal thinking and behavior… in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders,” and that youth should be “observed closely for clinical worsening, suicidality, or unusual changes in behavior.”2

The FDA's black-box warning is aimed at children and adolescents, but this past July the FDA issued a public health advisory on the use of antidepressants by adults, recommending they be “watched closely for worsening of depression and for increased suicidal thinking or behavior,” and that adults whose symptoms worsen while on antidepressants should be evaluated by their healthcare professional.3

The FDA developed the warning for youths based on a combined analysis of 24 short-term (up to four months) placebo-controlled trials of nine antidepressants that included more than 4,400 pediatric patients. The FDA reported in a public health advisory on October 15, 2004, that the average risk of suicidality was 4% in the studies reviewed, which was twice the placebo's risk. No actual suicides occurred during the trials.4

Some experts have criticized the FDA's rationale for requiring the black-box warning. One published analysis notes that not only did no suicides occur in the 4,400 patients, but that the definition of “suicidality” was unclear and that the data collected were not prospective.5 (A prospective study is specifically designed to look for outcomes and compares those outcomes with other factors such as suspected risk.) Another review claims that patients in drug trials (the type of patients the FDA studied) are not representative of typical patients in routine clinical practice.6

Centerstone's Dr. Rhea concurs with these views. “First, there were no suicides in the multiple trials that the FDA analyzed,” she says. “The only significant evidence was obtained by combining data—which violates usual FDA rules—for suicidal ideation and varying degrees of self-injury from multiple studies.”

The Effect

Nevertheless, the FDA's actions appear to have had an effect on prescribing, particularly for younger patients.7 The American Psychiatric Association reports an almost 20% decrease in antidepressant prescriptions for patients age 18 or younger during the year following the public advisory issued in March 2004. The public advisory was one of several announcements that appeared on the FDA Web site before the actual warning was issued in October 2004.

Before the FDA's actions, antidepressant and other psychotropic drug prescribing was increasing significantly, especially during the late 1990s. A recently published study from Brandeis University found a 250% increase in psychotropic medication prescribing among adolescents between 1994 and 2001, with the greatest increase occurring after 1999.8 The study's lead author, Cindy Parks Thomas, PhD, a senior scientist at the Schneider Institute for Health Policy at Brandeis, says prescribing increased the most during the late 1990s because of changes in federal advertising rules that allowed drug company representatives to disclose the use of psychotropic medications for off-label indications.

Regarding the risk of suicide with antidepressants, Dr. Thomas says, “The problem always is whether it is the underlying disease that causes suicide ideation, or is it the medication? There is differing opinion on this. Recent studies played down [antidepressants’] risk. However, the issue is still of sufficient concern that it is being examined further by the federal government.”

Dr. Thomas adds, “Benefits must always outweigh the risks before putting anyone on medication therapy. These medications in certain situations have had dramatic results in a very positive way. Prescribing has to be a considered decision in each case, between the professional, the parent, and/or the patient…. Medicated patients have to be very carefully monitored by experienced professionals, and the family must be aware of all potential side effects.”

Yet Centerstone's Dr. Rhea says some parents are focusing more on antidepressants’ possible risks than their benefits. She says that because of the black-box warning, parents are less likely to accept antidepressants as a treatment for their depressed children. “It is unfortunate that increasing numbers of depressed youth are untreated, especially since many are also undiagnosed,” notes Dr. Rhea.

Concerns About Bipolar Disorder

The FDA requires manufacturers to include on the labeling information for providers about ruling out bipolar disorder before prescribing antidepressants, because using antidepressants as monotherapy may lead to mania or hypomania. But even patients with bipolar disorder treated with antidepressants during depressive episodes do not appear to be at increased risk of suicide, according to another recent study.9

Investigators from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study followed 2,000 participants for 18 months. They found that out of the 425 who experienced a prospectively observed, new-onset major depressive episode without initial suicide ideation, 24 (5.6%) developed new-onset suicidality, and there were 2 suicide attempts at follow-up. Researchers found no association of new-onset suicidality with increased antidepressant exposure or any change in antidepressant exposure. They also found no association between suicide and starting antidepressant treatment.

Dr. Rhea says that bipolar depressed patients “may be shifted by antidepressants to a mixed state with irritability, agitation, and suicidal ideation. This is difficult to predict when the patient has not yet had a manic or hypomanic episode.” She adds that some patients with unipolar depression might have “an initial exacerbation of anxiety with insomnia and transient increased suicide risk. These and other situations require careful consideration and monitoring.”

Adelaide Robb, MD, medical director for inpatient psychiatry at Children's National Medical Center in Washington, D.C., and associate professor of psychiatry and behavioral sciences at George Washington University School of Medicine, testified for the American Academy of Child and Adolescent Psychiatry (AACAP) at a 2004 congressional hearing that reviewed data on antidepressants and suicide risk. Dr. Robb says that she frequently prescribes antidepressants to pediatric patients. But there are three groups of children or adolescents for which she avoids using antidepressants: those with bipolar depression, those whose parents refuse antidepressants (then she tries psychotherapy, but “revisits the need to medicate if necessary”), and in pregnant teenagers. Regarding the latter, Dr. Robb says, “We do not have enough data on effects on the fetus for most medications, including antidepressants.” In fact, use of antidepressants by pregnant women has become the latest controversy surrounding antidepressants (see sidebar).

Greater Awareness

In the final analysis, the FDA's warning for children and subsequent advisory for adults on antidepressant therapy have led to greater awareness of the power and potential of these drugs. Says Centerstone's Dr. Rhea: “We have made an effort to further engage therapists and case managers, as well as nurses, in more frequent and intensive monitoring of children and adolescents on antidepressants with regard to efficacy as well as safety.”

Theresa Waldron is a freelance writer.

References

1. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006; 163:41-7.
2. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. Labeling Change Request Letter for Antidepressant Medications. Rockville, Md.: FDA, October 15, 2004. Available at: www.fda.gov/cder/drug/antidepressants/SSRIlabelChange.htm.
3. U.S. Food and Drug Administration. FDA Reviews Data for Antidepressant Use in Adults. Rockville, Md.: FDA, July 1, 2005. Available at: www.fda.gov/bbs/topics/ANSWERS/2005/ANS01362.html.
4. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA Public Health Advisory: Suicidality in Children and Adolescents Being Treated With Antidepressant Medications. Rockville, Md.: FDA, October 15, 2004. Available at: www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm.
5. Klein DF. The flawed basis for FDA post-marketing safety decisions: The example of anti-depressants and children. Neuropsychopharmacology 2005; 30:2038-9.
6. Bostwick JM. Do SSRIs cause suicide in children? The evidence is underwhelming. J Clin Psychol 2006; 62:235-41.
7. American Psychiatric Association. Analysis confirms impact of FDA warning and raises concern for kids, APA says. Washington, D.C.: APA, September 2, 2005. Available at: www.psych.org/news_room/press_releases/05-53APAonPsychNewsAnalysis%20_3_.pdf.
8. Thomas CP, Conrad P, Casler R, Goodman E. Trends in the use of psychotropic medications among adolescents, 1994 to 2001. Psychiatr Serv 2006; 57: 63-9.
9. Bauer MS, Wisniewski SR, Marangell LB, et al. Are antidepressants associated with new-onset suicidality in bipolar disorder? A prospective study of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J Clin Psychiatry 2006; 67:48-55.
10. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006; 354:579-87.
11. Levinson-Castiel R, Merlob P, Linder N, et al. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med 2006; 160:173-6.
12. Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: A database analysis. Lancet 2005; 365:482-7.
13. U.S. Food and Drug Administration. Center for Drug Evaluation and Research. FDA Public Health Advisory: Paroxetine. Rockville, Md.: FDA, December 8, 2005. Available at: www.fda.gov/cder/drug/advisory/paroxetine200512.htm.
14. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006; 295:499-507.

Sidebar

ANTIDEPRESSANTS AND PREGNANCY

Another issue being addressed regarding antidepressants and children is the possible detrimental effects of SSRIs to newborns of mothers who take the medications while pregnant. The FDA most recently became concerned after a study was published in the February 9 issue of the New England Journal of Medicine, and at press time the FDA was considering its options.

The case-controlled study looked at SSRIs and the risk of persistent pulmonary hypertension (PPH) in newborns of mothers who had taken them during the last trimester of pregnancy.10 PPH is a clinical syndrome characterized by enlargement of the heart's right ventricle, which leads to blood flow resistance in the lungs and can cause heart failure. Investigators evaluated 377 women whose infants were born with PPH, comparing them with 836 matched control women and their infants. Fourteen infants with PPH had been exposed to an SSRI after the completion of the 20th week of gestation, compared with six control infants. However, mothers who took SSRIs before 20 weeks of gestation or who took non-SSRI antidepressants at any time during pregnancy did not give birth to infants with PPH.

In another recent study, researchers compared the prevalence and clinical characteristics of neonatal abstinence syndrome (NAS) in newborns exposed to SSRIs in utero.11 NAS is characterized by central nervous system hyperirritability, gastrointestinal dysfunction, respiratory distress, and vague autonomic nervous symptoms. The presence of those symptoms indicates physical dependence to a drug. The researchers evaluated 120 term infants, half of whom had been exposed for prolonged periods to an SSRI. The SSRIs studied were paroxetine (Paxil), fluoxetine (Prozac), citalopram (Celexa), sertraline (Zoloft), and venlafaxine (Effexor). The investigators assessed the infants using the Finnegan score for NAS.

Of the 60 newborns who had been exposed to an SSRI in utero, 8 had severe symptoms of NAS and 10 had mild symptoms of NAS. (The longest time interval an infant showed signs of NAS was four days after birth.) Because of the prevalence of NAS in the SSRI-exposed infants, the researchers concluded that newborns whose mothers take SSRIs should be monitored for at least 48 hours postpartum, and that the long-term effects of SSRIs on neonates “have yet to be determined.”

Dorothy E. Stubbe, MD, associate professor at the Yale University Child Study Center in New Haven, Connecticut, agrees. “We don't have all the answers about the long-term safety of these medications in infants,” she says. Dr. Stubbe says the three key issues with SSRIs in pregnant women are as follows:

• the “judicious use of medication, with careful weighing of the risks and benefits of the medication”;

• the “engagement of the pregnant woman as an active participant in the process”; and

• more research to “more fully inform our recommendations and treatment decisions.”

Dr. Stubbe adds that the SSRI that appears to be most closely associated with NAS is paroxetine.12 However, she says that central nervous system effects from SSRI withdrawal with any SSRI “appear to be short-term.” She recommends that if an SSRI is needed during pregnancy, clinicians try to use an SSRI other than paroxetine, since it is most highly correlated with NAS. The FDA has issued a public health advisory concerning use of paroxetine during pregnancy.13 Dr. Stubbe also recommends using the lowest dose possible of the SSRI to reduce risks to the baby.

Yet Dr. Stubbe adds, “Depression during pregnancy as well as postpartum depression is a very serious health risk. If SSRI use minimizes this risk, the health of the mother and the infant may be substantially improved. Serious postpartum depression may lead to psychosis, unintended neglect, or abuse of the baby, and it may interfere with long-term bonding between the mother-infant pair.”

A recent study in the Journal of the American Medical Association points to the benefits of using antidepressants during pregnancy, finding that major depression was much more likely to recur during pregnancy when women stopped taking antidepressants.14 The study, led by researchers in the Perinatal and Reproductive Psychiatry Clinical Research Program at Massachusetts General Hospital in Boston, was a prospective, naturalistic study using longitudinal psychiatric assessments on a monthly basis during pregnancy. The researchers also looked at survival analysis to determine time to relapse of depression during pregnancy.

Among 82 women who stayed on their medication throughout their pregnancy, only 21 (26%) relapsed compared with 44 (68%) of 65 women who discontinued their medication. Women who discontinued their medication were significantly more likely to relapse over the course of their pregnancy than were women who stayed on their medication. The researchers conclude that women with histories of depression who are euthymic during antidepressant therapy should be informed that they may have a relapse if they discontinue medication during pregnancy.

—Theresa Waldron