SSRIs, Akathisia, and Suicidality

Joseph Glenmullen, MD

Clinical Instructor in Psychiatry,

Harvard University

Author of Prozac Backlash

Press Briefing at the February 2, 2004 FDA Meeting on the Concern that SSRI Antidepressants Can Make Children and Adolescents Suicidal

Objective: To relate the data from studies of SSRIs to the realities faced by doctors and patients when SSRIs trigger suicidality

I have witnessed this side effect in patients who I treat with SSRIs

Akathisia and Suicidality—Side Effects of SSRIs

Diagnostic and Statistical Manual (DSM)

“Serotonin-specific reuptake inhibitor [SSRI] antidepressant medications may produce akathisia.”

A class effect of all SSRIs American Psychiatric Association 2000 Edition, p. 801

DSM (Continued)

“Akathisia may be associated with dysphoria [psychological distress], irritability, aggression, or suicide attempts.”

APA Textbook of Psychopharmacology “Akathisia, however, is the most

common neurological symptom caused by SSRIs.” p. 939

Edited by Schatzberg and Nemeroff

Second Edition, 1998, p.939

Based on Numerous Reports

American Journal of Psychiatry New England Journal of Medicine Archives of General Psychiatry Journal of Family Practice Journal of the American Academy

of Child and Adolescent Psychiatry Human Psychopharmacology Journal of Family Practice

The Two Faces of Akathisia

Well-known from antipsychotics, an earlier class of drugs

Outer, objective restlessness Inner, subjective agitation

Outer, Visible Restlessness

Mild: Adjust posture, shift weight, cross and uncross legs

Moderate: Visibly jittery, tap feet, pace

Severe: Ceaseless pacing, cannot sit or lie still

Inner, Subjective Agitation

Abject terror Anxiety Tension Irritability Hostility Paranoia Rage reactions Violence

Suicide Offers a “Welcome Relief” from Akathisia

Vulnerable Time Period

Early weeks or month after Starting the drug Increasing the dose

The Suicidality of Akathisia Is Distinctly Different from the Suicidality of Depression

Preoccupation with escape from the abject terror, anxiety, and irritability of physical and psychological state of akathisia versus preoccupation with the guilt, self-hatred,and hopelessness of depression

Treatment of Akathisia

Decrease dose Stop drug Add propranolol or Valium-type

antianxiety agent Switch to another class of

antidepressant

Brain Chemistry of SSRI Akathisia

The serotonin-dopamine connection

Antidepressants “selective” for serotonin appear to pose a greater risk of akathisia than other antidepressants

Other Side Effects of SSRIs that Increase the Risk of Suicide

Mania Insomnia Anxiety Paranoia Psychotic reactions

Primary Care Doctors Now Write 70% of Prescriptions for Antidepressants and Know Little about this Side Effect

Re-Challenge Studies

“Try the drug a second time” in patients who had the side effect to see if they experience it again

The best way to study and describe what actually happens to patients

Re-Challenge Studies of SSRIs Rothschild (Harvard) Journal of

Clinical Psychiatry,1991 Van Putten (UCLA) Archives of

General Psychiatry, 1992 Hamilton and Opler (Columbia)

Journal of Clinical Psychiatry, 1992

All the patients developed akathisia and suicidality again

Eli Lilly Agreed to Fund a Large Re-Challenge Study

Spring 1991 Reached agreement with the FDA

at the height of the crisis over this side effect in the early 1990s

Lilly developed the protocols for the study

Lilly never did the study

The September 1991 FDA Meeting on this Side Effect Is Widely Reported to Have Unanimously Exonerated SSRIs

But…

The FDA had to waive its own standards for conflicts-of-interest for 5 of the 9 committee members and 4 of the 6 consultants because of their ties to the pharmaceutical industry

On one of the votes taken by the committee, one-third of the committee members voted for a warning

Transcript of the 1991 FDA Meeting on this Side Effect

Dr. Nina Schooler: “We really do need to obtain more data…At one level” the data “is a fairly sorry state” because of its inability to adequately describe what happens to patients. Page 329

“Somehow, for me, the responses to this end up being always with that caveat…” Page 303

Transcript of the 1991 FDA Meeting on this Side Effect

Dr. John Mann: “I want to endorse [i.e. second] the need for better data.”

Page 298

Transcript of the 1991 FDA Meeting on this Side Effect

Dr. Daniel Casey (Chairman): “I know you [committee members]

want the caveat that ‘I don’t feel I have all the data.’”

Page 269 “There will be more research. At

least I certainly hope so.”

Page 297

January 2004 FDA Memorandum for this Meeting

12 years later the data is still: “a distinctly insensitive

approach…to [assessing] suicidality” and describing what actually happens to patients.

Page 7

January 2004 FDA Memorandum for this Meeting

The data is “generally inadequate.”

Page 17

January 2004 FDA Memorandum for this Meeting

“There is one caveat to this effort” because the data is of “unknown sensitivity” and “may have missed certain events” related to suicidality.

Page 15

January 2004 FDA Memorandum for this Meeting

12 years later, the FDA still wants “more adequate assessment for emergent suicidality in future studies.”

Page 17

For How Many Decades Are We Going to Get Together to Lament the Inadequacy of the Pharmaceutical Industry’s Efforts to Clarify this Phenomenon?

The Industry Response

Dismiss serious medical case reports and small-scale studies, which are all solo practitioners can afford to do, as “anecdotes”

The Industry Response

Blame patient’s psychiatric conditions

The Industry Response

Scare the media and other interested parties away from the subject by citing a fear that patients will be frightened away from treatment

Authoritarian Approach

Don’t warn patients, you might frighten them

The most dangerous scenario:

When neither the doctor nor the patient knows about akathisia

What if you were considering an SSRI for your child?

If you would want to be informed about this side effect if you were considering an SSRI for your child, please use your power as journalists to inform the public.