Paper Outline

ANTIDEPRESSANTS AND SUICIDE

Further evidence of increased suicide risk with antidepressants in children

ccording to a new case-control study, antidepressant treatment may increase

the risk of suicide in severely depressed chil- dren and adolescents, but not in adults. Sui- cide attempt risk among young people hospi- talized for depression and treated with antide- pressants was 1.5 times greater than among comparable groups of children who received no antidepressant treatment.

No significant associations were found between adults who received antidepressant treatment and suicide attempt or suicide death following hospital discharge.

The study, led by Mark Olfson, M.D., and published in the August issue of Archives of General Psychiatry, is unique in being the first large-scale analysis comparing suicide attempts and suicide deaths in adults and chil-

linicians face a particular challenge when treating pregnant women with

mood and anxiety disorders, write Shaila Misri, M.D., clinical professor of psychiatry and OB/GYN, University of British Colum- bia, and colleagues in a study appearing in the American Journal of Psychiatry. They have to balance the consequences of exposure to unstable maternal mood and anxiety with the risks of prenatal exposure to psychotropic medications.

The authors followed children who were exposed prenatally to psychotropic medica- tions for four years and found no association with increased reports of internalizing behav- iors at age 4. The authors did find, however, that impaired maternal mood had an identifi-

able impact on child behavior. Children with internalizing behaviors often go unrecognized and receive inadequate treatment. After a

PRENATAL DRUG EXPOSURE: SPECIAL REPORT

No link between prenatal drug exposure and internalizing behaviors in young children

PRENATAL EXPOSURE, continued on page 6

VOLUME 8, NUMBER 10 OCTOBER 2006 ISSN 1527-8395 ONLINE ISSN 1556-7567

Editor: Henrietta L. Leonard, M.D.

Highlights… This month we bring you an update on the latest data regarding whether antidepressant use is linked to suicide in children and adolescents. Mark Olfson, M.D., talked with us about the results of his study.

For special coverage of neonatal drug exposure, see pages 1, 3, 4, 5, and 8.

Inside WHAT’S NEW IN RESEARCH . 3 • Prenatal exposure to SSRIs and/or

maternal depression • Prenatal exposure to mirtazapine

and birth outcomes

NEWS NOTES. . . . . . . . . . . . 7

CASE REPORT . . . . . . . . . . . 8 • Elevated neonatal gamma-

glutamyl transpeptidase with maternal lamotrigine use

FROM THE FDA . . . . . . . . . 8

A

C

précis • New findings suggest antidepressant treat-

ment may increase suicidality in children and adolescents, but not in adults

• Case-control study comparing suicide attempts and suicide deaths among 878 Medicaid inpatients (ages 6 to 64 years) with severe depression, treated or not treated with antidepressants, and matched to 4,070 controls

• Nearly two thirds of all suicide attempts or suicide deaths occurred within 4 months of hospital discharge; nearly 75% occurred within the first 6 months following dis- charge

• Results are consistent with recommenda- tions for close monitoring for clinical wors- ening during acute phase of antidepressant treatment in pediatric patients

précis • Prospective analyses find little variation in

internalizing behaviors between 4-year- olds with and without in-utero exposure to an SSRI

• Increased parental reports of child internal- izing behaviors associated with maternal symptoms of depression and anxiety

• Researchers emphasize importance of monitoring long-term behavioral outcomes of children exposed in utero to psychotrop- ic medications and born to mothers with chronic mental illness.

• FREE PATIENT HANDOUT: MIRTAZAPINE (GENERIC) – REMERON (BRAND) •

SUICIDE RISK, continued on page 2

Published online in Wiley InterScience (www.interscience.wiley.com)

DOI: 10.1002/cpu.20029

2 THE BROWN UNIVERSITY CHILD & ADOLESCENT PSYCHOPHARMACOLOGY UPDATE OCTOBER 2006

Editor: Henrietta L. Leonard, M.D., Professor of Psychiatry, Brown Uni- versity; Director of Training, Child and Adolescent Psychiatry, Rhode Island Hospital, Providence, RI.

Guest Editor....Christopher Kratochvil, M.D.

Executive Editor..................Karienne Stovell

Associate Editor .......................Sarah Merrill

Associate Editor......................Diana Steimle

Contributing Writer.......................Gary Enos

Production Editor................Matthew Hoover

Editorial Director ............Jo-Ann Wasserman

Publisher.......................................Sue Lewis

Business/Editorial Office: John Wiley & Sons, Inc., 111 River St., Hoboken, NJ 07030-5774 (201) 748-8824

Reader Fax: (201) 748-8824

E-mail: [email protected]

Customer Service and Subscription Information: Phone (888) 378-2537; Fax (888) 481-2665

Wiley InterScience Subscription Information: 800-825-7550

The Brown University Child and Adolescent Psychophar-

macology Update does not offer specific medical advice.

We encourage subscribers to seek advice from qualified

professionals.

The Brown University Child and Adolescent Psychophar-

macology Update is published monthly by Wiley Sub-

scription Services, Inc., A Wiley Company, 111 River St.,

Hoboken, NJ 07030-5774; e-mail: [email protected].

Annual subscription rate is $199 for individuals and

$1,085 for institutions. Periodicals postage paid at Provi-

dence, RI. POSTMASTER: For address changes, contact

Subscription Distribution US, c/o John Wiley & Sons,

Inc., 111 River Street, Hoboken, NJ 07030-5774. © 2006

Wiley Periodicals, Inc., A Wiley Company. All rights

reserved. Reproduction in any form is strictly forbidden

without consent of the publisher. For reprint permission,

contact the reprint coordinator, at (201) 748-6011.

Photo: Jill Brody

dren treated or not treated with antidepres- sants. While the findings provide addition- al data supporting an association between antidepressant treatment and suicide risk in young people, the reasons for the associa- tion are less clear. Olfson is Professor of Clinical Psychiatry, New York State Psy- chiatric Institute/Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY.

The results are consistent with an FDA meta-analysis1 of 24 clinical trials which found a higher risk of suicidal thinking and behavior among children treated with antidepressants compared with children not treated with antidepressants. In Octo- ber 2004, the FDA directed pharmaceuti- cal manufacturers of all antidepressant medications to include a “black box” warning of increased suicidality in chil- dren and adolescents treated with antide- pressants. Fluoxetine (Prozac) is currently the only antidepressant approved for treat- ment of depression in pediatric patients.

The findings also support current rec- ommendations2-3 for close monitoring of clinical worsening, including irritability, agitation, suicidality, and unusual behav- ioral changes during antidepressant treat- ment.

Study details Olfson and his team designed the two-

year matched-control study based on a rel- atively homogenous population. “By lim- iting the analysis to patients after inpatient treatment of depression, we sought to ensure that cases (suicide attempt and sui- cide death) and controls (no suicide attempt and no suicide death) who did or did not receive antidepressant treatment had a high and comparable level of illness severity,” write Olfson and colleagues.

The study was based on an analysis of 878 cases of Medicaid beneficiaries (ages 6 to 64 years) throughout the United States who received inpatient treatment for a depressive disorder and subsequently attempted or completed suicide, matched to 4,070 controls. The reference period was from January 1, 1999 through December 31, 2000. Patients with claims for pregnan- cy, bipolar disorder, schizophrenia or other psychoses, mental retardation, or demen- tia/ delirium were excluded from the study cohort. The date of a suicide attempt or sui-

cide death was defined as the event date. Cases were excluded for patients who received 15 days or more of inpatient treat- ment within 60 days before the event date.

Among patients who attempted suicide, 784 cases were matched to 3,635 controls. For completed suicides, 94 cases were matched to 435 controls. Criteria for match- ing cases and controls were the same for sui- cide attempts and completed suicides. Each case was individually matched to up to 5 controls by age, sex, race/ethnicity, date of hospital discharge, and state providing Med- icaid services. Controls were also matched to cases based on claims of substance abuse disorder, recent suicide attempt and use of antipsychotics, anxiolytic/hypnotics, mood stabilizers and stimulants.

Cases and controls were classified ac- cording to whether they received antide- pressant medication treatment or not, with treatment defined as a prescription for an antidepressant drug covering the days that included or exceeded the event date.

The antidepressant drug groups includ- ed selective serotonin reuptake inhibitors (SSRIs), including citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; or other antidepressants (including bupropi- on, mirtazapine, nefazodone, trazodone, venlafaxine, and tricyclic antidepressants). The tricyclic antidepressants included sec- ondary and tertiary tricyclic antidepres- sants, as well as the tetracyclic antidepres- sants amoxapine and maprotiline. During the two-year reference period no cases or controls used monoamine oxidase inhi- bitors.

The main outcome measures were sui- cide attempt or completed suicide with patient antidepressant medication prescrip- tion as the independent or predictor variable.

Three conditional logistic regressions

SUICIDE RISK continued from page 1 “Child psychiatrists must

grapple with the clinical challenge of balancing safety concerns against the risks of not treating

young people at high risk.” Mark Olfson, M.D.

OCTOBER 2006 THE BROWN UNIVERSITY CHILD & ADOLESCENT PSYCHOPHARMACOLOGY UPDATE 3

were used for analysis, with no antidepres- sant treatment as the reference group: (a) comparison of any antidepressant treat- ment with no antidepressant treatment; (b) comparison of SSRIs, venlafaxine, mir- tazapine, bupropion, trazodone, nefa- zodone, and tricyclic antidepressants with no antidepressant treatment; and (c) com- parison of each SSRI with no antidepres- sant treatment.

Results Among children and adolescents (mean

age 15.4 ± 1.8 years), there were 263 cases of attempted suicide, and 8 cases (mean age 16.1 ± 1.5 years) of completed suicide. For children under the age of 12 years, there were 13 cases (1.7%) of attempted suicide, but no completed suicides.

There was a significant association between children and adolescents treated with antidepressants and attempted suicide (odds ratio [OR]=1.52; 95% confidence interval [CI] 1.12-2.07]; 263 cases and 1,241 controls) and with suicide deaths (OR=15.62; 95% CI 1.65-infinity; 8 cases and 39 controls).

Children and adolescents were signifi- cantly more likely to attempt suicide if they had been treated with sertraline (p=0.003), venlafaxine (p=0.007) or tri- cyclic antidepressants (p=0.002) than those not treated with antidepressants (see Table 1).For the 8 children and adoles- cents who completed suicide (mean age 16 years), they were significantly more likely than controls to have been treated with an SSRI (37.5% vs 7.7%; p=0.005).

There was no significant association between the likelihood of attempting sui- cide and antidepressant treatment in adults.

For adults who committed suicide, approximately 52% had been treated with hypnotics, 23% with antipsychotics, and 17% with mood stabilizers within 60 days prior to their death. No children or adoles- cents treated with these medications died by suicide within the 60-day time period.

Nearly two thirds of all suicide attempts or suicide deaths occurred early after hospital discharge (in the first 4 months), and nearly 75% of suicide attempts and deaths occurred in the first 6 months following hospital discharge.

Since the current study was limited to patients immediately following hospital discharge for depression — a period of high risk — the results “tell us nothing

about the safety or effectiveness of antide- pressant treatment during lower-risk peri- ods,” Olfson told The Update.

One of the limitations of this case-con- trol study is that antidepressants may be prescribed to youth who are more severely depressed and, therefore, at increased risk of suicide. Although the cohort excluded patients with comorbid conditions that are known to affect risk of suicide (e.g., bipo- lar disorder and schizophrenia), with close matching of cases to controls using demo- graphic and medical criteria, Olfson and colleagues suggest that “the possibility of confounding illness severity of antidepres- sant drug treatment selection persists.”

The results are also limited by having used a relatively small sample of select suicide cases; the lack of matching cases to controls on factors such as family histo- ry of suicide, and stressful conditions lead- ing up to the suicide event; the lack of pill counts or electronic measures which may have yielded more accurate information on medication use; the accuracy of the cate- gory of death by suicide which because of religious beliefs or social stigma may con- tribute to underreporting; limiting the analysis to Medicaid beneficiaries whose pharmacological treatment may vary from patients who are private insured; and an upper age limit of 64 years.

Clinical implications The results of this study highlight the

importance of closely monitoring young patients for changes in mood or behavior after they begin antidepressant treatment, said Olfson.

In a practice setting, “child psychia- trists must grapple with the clinical chal- lenge of balancing safety concerns against the risks of not treating young people at high risk.” One of the key challenges that lies ahead will be to identify young patients who are most likely to benefit from antidepressant treatment and those who are “sensitive to the negative effects of antidepressants,” said Olfson. J • • • • • • • • • • • • • • • • • • • • • • • • • • • *Funded by grants from the National Alliance for Research on Schizophrenia and Depression, the American Foundation for Suicide Prevention, Agency for Healthcare Research and Quality, and the Carmel Hill Fund.

Olfson M, Marcus SC, Shaffer D: Antidepressant drug therapy and suicide in severely depressed children and adults. Arch Gen Psychiatry 63(8):865-872. E-mail: [email protected].

REFERENCES

Hammad TA, Laughren T, Racoosin J: Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry 2006; 63(3):332-339.

FDA Public Health Advisory. Suicidality in children and adolescents being treated with antidepressant medications. October 15, 2004. www.fda.gov/cder/drug/antidepressants/ SSRIPHA200410.htm

Antidepressant use in children, adolescents, and adults. www.fda.gov/cder/drug/antidepressants

Table 1. Association of pediatric suicide attempt with antidepressant treatment Antidepressant % Cases* % Controls** p value§ Odds ratio (95% CI)

Fluoxetine 4.9 6.9 0.16 0.69 (0.35-1.37)

Paroxetine 9.9 7.4 0.27 1.36 (0.80-2.30)

Sertraline 12.9 7.7 0.003 1.88 (1.15-3.06)

Citalopram 2.3 3.8 0.21 0.68 (0.28-1.67)

Fluvoxamine 0.4 0.3 0.92 0.91 (0.09-8.93)

Tricyclic agents 4.2 1.4 0.002 3.09 (1.32-7.22)

Venlafaxine 7.2 3.4 0.007 2.33 (1.25-4.33)

Mirtazapine 3.8 2.1 0.13 1.64 (0.68-3.94)

Bupropion 4.9 4.6 0.97 1.07 (0.53-2.19)

Trazodone 4.9 4.0 0.59 0.86 (0.35-2.42)

Nefazodone 2.3 1.1 0.27 1.62 (0.58-4.53)

* N=263 ** N=1,241 § statistical significance > 0.05 Table adapted from Olfson et al., 2006.

CE/CMEs now available through The Update

You can now take CE/CMEs for reading your copy of The Brown University Child &

Adolescent Psychopharmacology Update.

Go to www.CEQuick.com for more details.