SSRIs, Akathisia, and Suicidality

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SSRIs, Akathisia, and Suicidality

• Joseph Glenmullen, MD
• Clinical Instructor in Psychiatry,
• Harvard University
• Author of Prozac Backlash

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Press Briefing at the February 2, 2004 FDA
Meeting on the Concern that SSRI Antidepressants
Can Make Children and Adolescents Suicidal
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Objective To relate the data from studies of
SSRIs to the realities faced by doctors and
patients when SSRIs trigger suicidality
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I have witnessed this side effect in patients who
I treat with SSRIs
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Akathisia and SuicidalitySide Effects of SSRIs
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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

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DSM (Continued)

• Akathisia may be associated with dysphoria
  psychological distress, irritability,
  aggression, or suicide attempts.

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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

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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

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The Two Faces of Akathisia

• Well-known from antipsychotics, an earlier class
  of drugs
• Outer, objective restlessness
• Inner, subjective agitation

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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

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Inner, Subjective Agitation

• Abject terror
• Anxiety
• Tension
• Irritability
• Hostility
• Paranoia
• Rage reactions
• Violence

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Suicide Offers a Welcome Relief from Akathisia
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Vulnerable Time Period

• Early weeks or month after
• Starting the drug
• Increasing the dose

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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

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Treatment of Akathisia

• Decrease dose
• Stop drug
• Add propranolol or Valium-type antianxiety agent
• Switch to another class of antidepressant

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Brain Chemistry of SSRI Akathisia

• The serotonin-dopamine connection
• Antidepressants selective for serotonin appear
  to pose a greater risk of akathisia than other
  antidepressants

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Other Side Effects of SSRIs that Increase the
Risk of Suicide

• Mania
• Insomnia
• Anxiety
• Paranoia
• Psychotic reactions

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

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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

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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

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

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Transcript of the 1991 FDA Meeting on this Side
Effect

• Dr. Nina Schooler We really do need to obtain
  more dataAt 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

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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

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Transcript of the 1991 FDA Meeting on this Side
Effect

• Dr. Daniel Casey (Chairman)
• I know you committee members want the caveat
  that I dont feel I have all the data.
• Page 269
• There will be more research. At least I
  certainly hope so.
• Page 297

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January 2004 FDA Memorandum for this Meeting

• 12 years later the data is still
• a distinctly insensitive approachto assessing
  suicidality and describing what actually happens
  to patients.
• Page 7

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January 2004 FDA Memorandum for this Meeting

• The data is generally inadequate.
• Page 17

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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

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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

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

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

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The Industry Response

• Blame patients psychiatric conditions

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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

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Authoritarian Approach

• Dont warn patients, you might frighten them

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The most dangerous scenario When neither the
doctor nor the patient knows about akathisia
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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.