SSRIS: DO THEY CAUSE SUICIDE

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SSRIS DO THEY CAUSE SUICIDE?
Yolande LucirePhD, MB BS DPM FRANZCPSchool of
Rural Health, Albury NSWForensic Psychiatrist.
Woollahra Sydney
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Antidepressants form two major groupings New
SSRIs and older TCAs, which Ill call
TricyclicsSSRIs act on Serotonin and have
profound effects. They are capable of changing
people profoundly and not always for the best.
Contrary to popular opinion, there is no
scientific evidence that serotonin is abnormal in
depression.Having more of it floating around
makes for a lot of change.
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SSRIs (the Accused) TCAs (the Comparator)
Prozac
Tryptanol Zoloft
Tofranil Aropax Prothiaden
Efexor SinequanCipramilLexaproLuvox
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For the purpose of a 20 minute presentation, I am
grouping the drugs that act on serotonin together
and calling them SSRIs, although some are SSRIs
and some are SNRIs and others have mixed actions.
For the purpose at hand, suicide induction or
completed suicide they all have a similar
profile, with the more energising ones possibly
more heavily implicated. Suicide is the
measurable tip of an iceberg of disturbance
violence and disturbance, and may have come about
in a variety of ways. Similarly the TCA are not
only tricyclics but tetracyclics and some
atypical ones, in general not having an action on
serotonin.
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CautionDo not stop taking an antidepressant
without medical supervision.Complications occur
on starting, stopping and with irregular dosing.
Withdrawal can start up to four weeks after
stopping the drug and can go on for three months
Complications include agitation, mania,
psychosis and self harm and suicide and violence
and homicide.
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The possibility that a drug was causing the
effects it was supposed to cure was unthinkable,
especially by clinicians.But it is accepted
SSRI-induced akathisia is in the latest
Diagnostic and Statistical Manual, the ever
expanding list of mental disorders. DSM
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How common is it?A 2001 Yale 8 of patients
admitted may suffer from SSRI-induced mania or
psychosis.Higher levels of prescribing in OZ
and including agitation, suicidal thoughts and
attempts, its more like 20.
Preda A, MacLean RW, Mazure CM, Bowers MB (2001).
Antidepressant associated mania and psychosis
resulting in psychiatric admission. J Clinical
Psychiatry 62, 30-33
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I will give you Daubert competent science.
Science that has passes 6 Daubert
Hearings.Scientific (as opposed to opinion)
evidence is the only kind of expert evidence
admissible in American and Australian courts
Scientific evidence that SSRIs cause
Suicidal thinking Suicidal acts
Completed suicide.
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The 1993 US Supreme Court Decision in Daubert v.
Merrell Dow Pharmaceuticals altered the criteria
by which scientific testimony is admitted as
evidence in court. The unanimous ruling states
that the criterion of the scientific status of a
theory is that it can be tested, refuted and
falsified.Scientific method is based on
generating a null hypothesis, a conjecture that
something does not exist, and testing it to see
if it you can prove the contrary.The unicorn
does not exist. The prisoner is not guilty. These
are respectively good science and good law
Disproving the negative differentiates science
from other forms of inquiryWilliam Daubert, et
ux., etc., et al., Petitioners v. Merrell Dow
Pharmaceuticals, Inc.Supreme Court of the USA,
June 28, 1993.
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We need to watch two numbers RELATIVE RISK
RR SUICIDE RATE /100,000
The null hypothesis isSSRIs DO NOT CAUSE SUICIDE
And the range, which is the CONFIDENCE INTERVAL
CI indicating reliability
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A Relative Risk, RR, is how many more times
SUICIDE and its precursors THINKING OF SUICIDE
AND SUICIDAL ATTEMPTSoccur in SSRI-TREATED
PATIENTS over and abovethose treated with a
Tricyclicor not treated at all.
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If a medicine saves some depressed patients
from committing suicide, the RR between that
medicine and no treatment should be less than
1.Tricyclics generally had an RR of 0.5
against no treatment, in hospital depressions,
in which suicides were a known risk. Tricyclics
halved the number of suicides in a seriously
depressed population.
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Tricyclics were known to cause suicide by
energising the depressed, but RR was still
favourable.If the relative risk equals 1.0, the
risk in treated individuals is the same as the
risk in untreated ones. If the relative risk is
more than 1.0, the risk in treated is greater
than in untreated.As we are trying to prevent
suicide, an RR of 1 would be ominous.
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Eli Lilly (Prozac) Pfizer (Zoloft) and GSK
(Aropax) proposed in 1999, the cut off point of
SIGNIFICANCE, Relative Risk, RR, be 2.0.
Ridiculously HIGH by any standard. Corporate
chutzpah.
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Exposure to asbestos is deemed contributory to
cancer if the RR is only 1.2 which is 20
higher. Asbestos was never expected to PREVENT
cancer. AN RR OF 2 IS FIVE TIMES THAT.
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The evidence for suicide induction can be found
in many areas of research1. CLINICAL
PSYCHIATRY Observations and mechanisms Challen
ge-Dechallenge-Rechallenge experiments Studies
of NEW suicidal ideation, (Fava)2. SUICIDE
EPIDEMIOLOGY SUICIDES BY PRESCRIBED DRUG
JICK, UK DSRU DONOVAN POPULATION
STUDIES , PRIMARY CARE HEALY AND
BOARDMAN3. HEALTHY VOLUNTEER STUDIES 4. RANDOM
CONTROL TRIALS (RCTs) The evidence from all
these sources is overwhelmingly supports a
relative risk of suicide by SSRI users of greater
than 2, and sometimes as high as 8 or 10.
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CLINICAL PSYCHIATRY 1990American Journal of
Psychiatry. 147(2)207-10, 1990 Feb.Abstract
Teicher Glod and Cole. Six developed intense,
violent suicidal preoccupation after 2-7 weeks of
Prozac which persisted 3 days to 3 months after
Prozac was stopped. None had ever experienced a
similar state .Drug companies called this
anecdotal and said Its the disease not the
drug, doctor Now scores of such reports,
patients treated for anxiety, eating
disorders,OCD and menstrual problems and children
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CLINICAL PSYCHIATRYTeicher and Cole (1993)
delineate 9 clinical mechanisms by which SSRIs
can induce or exacerbate suicidal tendencies by
(1) energizing depressed patients, (2)
paradoxically worsening their depression , (3)
inducing akathisia, (4) inducing panic attacks,
(5) switching patients to mania or hypomania,
(6) causing insomnia or interfering with sleep
architecture (esp. with REM sleep), (7) inducing
an organic obsessional state, (8) promoting
personality disorder with borderline traits, (9)
producing EEG or other neurological disturbances.
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Those at risk of suicide are agitated,in turmoil,
nervous, sleepless, pacing, energized, almost
manic, and they reject their obsessive suicidal
thoughts as strange, weird,not me.This
can go on for weeks orcan turn into suicide
unpredictably in a matter of minutes.Teicher
and Cole, 1993 Healy, Langmaak, and Savage,
1999
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The traditional suicidogenic triumvirate of
psychotropic drug reactions are 1) akathisia,
(2) emotional blunting, also called psychic
numbing I cannot feel anything, do not care
and/or (3) psychotic decompensation Akathisia
is turmoil, feeling numb as if nothing matters,
and feeling one is going mad. It can happen
over weeks or days, or very very quickly, in a
matter of minutes. Teicher and Cole, 1993
Healy, Langmaak, and Savage, 1999
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CLINICAL PSYCHIATRY1991 Suicidal thinking (out
of the blue)Fava and Rosenbaum found suicidal
thinking developed in patients who had never been
suicidal before, more on Prozac than on other
drugs. Prozac v TCAs RR 2.7Scores of
reportsFava, M. Rosenbaum, J. 1991. Suicide
and 3 fluoxetine. Journal of Clinical
Psychiatry, 52-5.
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CLINICAL PSYCHIATRYSUICIDAL ACTS2 of 26
depressed patients overdosed in the first 2
weeks when Prozac was increased quickly. 7.6
is an extremely high rate. M. Muijen, et al., A
Comparative Clinical Trial of Fluoxetine,
Mianserin, and Placebo in Depressed Outpatients,
Acta Psychiatrica Scandinavica, Vol. 78 (1988),
pgs. 384-390).
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CLINICAL PSYCHIATRYChallenge-Dechallenge-Rechalle
nge CDRThere are many Challenge-Dechallenge-Rech
allenge studies. Suicidality starts on drug,
clears up when it is stoppedand Reappears
on re-exposure, even to another SSRI.
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SUICIDE EPIDEMIOLOGY JICKAgainst concerns that
Britains most popular TCA antidepressant,
Prothiaden, dangerously toxic in overdoseand
being labeled as a dirty drug by SSRI mfrs.Jick
examined172,598 persons and 1.2 million scripts
for 10 antidepressants, old and new, general
practice patients143 had committed
suicide.Jick S, Dean AD, Jick H (1995).
Antidepressants and suicide. British Medical
Journal 310 215-218
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SUICIDE EPIDEMIOLOGY JICKProthiaden turned out
to be the safest as only 14 of suicides involved
antidepressant overdose.RR of SUICIDE Prozac
v all TCAs RR 6.6 Prozac v Tofranil RR
1.9 Prozac v Amitriptyline RR 4.0
Prozac v Prothiaden RR 2.1 Prozac v
Lofepramine RR 4.04SSRI overdoses are
not fatal. SSRI suicides tend to be violent
hanging, drowning, shooting, jumping, stabbing or
cutting, dying on a railway, burning,
electrocution, or deliberate road accidents.
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SUICIDE EPIDEMIOLOGY JICK Jick was
embarrassed and suggested that selected
patients may have been given Prozac, which had a
high suicide rate attached.
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SUICIDE EPIDEMIOLOGY DRUG SAFETY RESEARCH UNIT
UK (50,000 pop.)The DSRU follows up drugs in
the communityit looked at completed suicides
and what medicines they had been
prescribed.Suicide rate on SSRIs
219/100,000.Prozac 244/100,000Aropax
269/100,000Luvox 183/100,000
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SUICIDE EPIDEMIOLOGY
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Boardman and Healy investigated 475,000 over 5
yearscounting all the mood disorders in all the
private practices and suicide rates for these
disorders
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Boardman Healy
SUICIDE EPIDEMIOLOGY
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SUICIDE EPIDEMIOLOGY Boardman HealyPRIMARY
CARE SUICIDE RATES All mental disorders 27-67/100,000. Fits in with other primary care
mood disorders suicide statistics Holland
30/100,000 Sweden 0/100,000Antedating
SSRIs Simon, von Korff 30/100,000 Highest UK
rate 68/100,000Boardman AP, Healy D.
Madeley suicide risk in primary care primary
affective disorders. European Psychiatry. 2001
16 400-405.
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SUICIDE EPIDEMIOLOGY DONOVAN again sought to
establish the safety of SSRIs against TCAs which
were toxic in overdose. Examined 222 COMPLETED
SUICIDES, and the medicines they had been taking,
and found SSRIs v TCA RR 2
Donovan S, Kelleher MJ, Lambourn J, Foster R.
The occurrence of suicide following the
prescription of antidepressant drugs. Arch Suic
Res. 1999 5 181-192.
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SUICIDAL ACTS DONOVANAt the same time, DONOVAN
looked at 2776 acts of DELIBERATE SELF HARM in
1954 persons presenting to emergency and what
they were taking Aropax v Tryptanol (TCA) RR
4.0 Prozac v Tryptanol (TCA) RR 6.6
Zoloft v Tryptanol (TCA) RR 4.9
Aropax v Tofranil (TCA) RR 1.9 All
SSRI v Tofranil (TCA) RR 5.5 Donovan S,
Clayton A, Beeharry M, Jones S, Kirk C, Waters K,
Gardner D, Faulding J, Madely R. Deliberate
self-harm and antidepressant drugs.
Investigation of a possible link. Brit J
Psychiatry. 2000 177 551-556
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HEALTHY VOLUNTEERSHealy 2 of 20 healthy
volunteers suicidal on Zoloft.
Healthy Volunteer Studies DRUG
PUBLISHED DONE PROZAC 12
of 53 AROPAX 14 of 35 ZOLOFT
7 of 35
1 healthy volunteer suicide in an Aropax trial
was not reported
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2 healthy volunteers have suicided19 year old
Traci Johnston, a healthy volunteer,suicided
February 7th 2004 in a trial of Eli Lilly's new
Serotonin drug - duloxetine, for
incontinenceaborting the trialReported in
Sydney Morning HeraldLilly had been doing
clinical trials in Australia
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ResultYou cannot set up a trial to see how
many people kill themselves as a consequence of
the drug you are testingIt would be impossible
to get insuranceor ethics approval. Or
informed consent? Have to
make do with information we have.Emergence of
antidepressant suicidality, published in 2000 in
Primary Care Psychiatry (Vol. 6, No. 1).
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RANDOM CONTROLLED TRIALS (RCTs)SUICIDES AND
SUICIDAL ACTS2003, Khan et al. looked atBLIND
CLINICAL TRIALS from 1986-90 Presented to the
US Federal Drug Administration, to get SSRIs
licensed. FOR9 Serotonin ANTIDEPRESSANTS
against comparators and placebos.
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Kahn found NO DIFFERENCE in suicides and
suicidal acts between those on SSRIs or on
COMPARATOR DRUGS or PLACEBOS48,277 depressed
patients participated in the trials,and 77
committed suicide. Thats a lot. Am J
Psychiatry. 2003 Apr160(4)790-2.
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RANDOM CONTROLLED TRIALS SSRIs had failed to
demonstrate usefulness in hospital depressions.
(We still give as much ECT as we ever did) so
hospital patients carrying suicide risk were
not recruited into these trials.SSRIs were
aimed at general practice. Samples of
convenience patients under stress, with minor
disorders, The Valium using population of the
1970sWith suicidal patients filtered out.
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In September of 2003, Healy and Whittaker
re-evaluated the same, original FDA studies.
They published a watershed paper in September
2003. Antidepressants and suicideriskbenefit
conundrumsDavid Healy, MD Chris Whitaker,
MScHealy Department of Psychological Medicine,
University of Wales College of Medicine, Hergest
Unit Whitaker Department of Informatics,
University of Wales Bangor, Bangor, United
Kingdom. J Psychiatry Neurosci 200328(5)331-7
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Whereas Kahn had coded as placebo suicides
those within 2 weeks of stopping an SSRI Healy
and Whittaker recognised these 5 SUICIDESand
MANY SUICIDAL ACTS AS SSRI WITHDRAWAL
SUICIDES.
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Khan had countedsuicides per number of patient
years exposed to the drug, PEYs.Healy counted
suicides per number of patients treated
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Healy argued that the risks of SSRIs resembled
the risks of space travel which, mile for mile,
was the safest form of transport available.
But going up and coming down are the danger
periods for both.
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But landing and re-entry occurs each time a dose
is forgotten, not absorbed, taken with alcohol
or if a co-prescribed medicine is added or
removed.
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Incidence of Suicides and Attempts in Trials From
FDA Medical Reviews
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Summary Incidence of Suicides and Suicide
Attempts (combined) in Antidepressant Trials From
FDA Medical Reviews
Healy D, Whitaker CJ (2003). Antidepressants and
suicide Risk-Benefit Conundrums. J Psychiatry
Neuroscience 28 (5) 331-339, with response by Y
Lapierre 340-349.
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FDA TRIALS SUMMARY 26,000 subjects SUICIDE
RATESALL DRUGS SUICIDE 232/100,000SSRI
SUICIDE 186/100,000 PLACEBO SUICIDE
64/100,000RELATIVE RISK FDA TRIALSSUICIDE ON
SSRI RR 2.4 (CI 0.6-10.2)SUICIDAL ACT ON
SSRIS RR 2.2 (CI 1.4-3.5)S/ ACTS ON NEW
ANTIDEPRESSANTS RR 4.3 (CI 1.1-17.8)
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SUICIDE RATESDRUG SAFETY RESEARCH UNIT SSRI
SUICIDE 212/100,000JICK PROZAC in
first 30 days of treatment 274/100,000
PEYsPROZAC 93/100,000
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SUICIDE EPIDEMIOLOGY Boardman Healy and many
othersAntedating SSRIsPRIMARY CARE SUICIDE
RATES POPULATION STUDY 68/100,000Boardman AP,
Healy D. Madeley suicide risk in primary care
primary affective disorders. European
Psychiatry. 2001 16 400-405.
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Healy and Whittakers conclusion was modest
It is no longer possible to support the null
hypothesis that SSRIs do not cause suicide The
null hypothesis has been falsified.
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Any way you look at available information,
clinical settings,emergency rooms, morgues,
clinical trials,SSRIs as a general cause of
suicide would pass the scientific standard of
proof.The BMJ issued warnings on February 5
2004.FDA on March 23Most manufacturers put on
Websites on May 3, 2004. Only in USA.
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FDA Public Health Advisory March 22,
2004 Subject WORSENING DEPRESSION AND
SUICIDALITY IN PATIENTS BEING TREATED WITH
ANTIDEPRESSANT MEDICATIONS Today the Food and
Drug Administration (FDA) asked manufacturers of
the following antidepressant drugs to include in
their labeling a Warning statement that
recommends close observation of adult and
patients treated with these agents for worsening
depression or the emergence of suicidality. The
drugs that are the focus of this new Warning are
Prozac (fluoxetine) Zoloft (Sertraline) Paxil
(paroxetine) Luvox (fluovoxamine) Celexa
(citalopram) Lexapro (escitalopram) Wellbutrin
(bupropion) Effexor (venlafaxine) Serzone
(nefazodone)
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WARNING MAY 3 2004 patients being treated with
antidepressants should be observed closely for
clinical worsening and suicidality, especially at
the beginning of a course of drug therapy, or at
the time of dose changes, either increases or
decreases.
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WARNING MAY 3 2004 Families and caregivers of
patients being treated with antidepressants for
major depressive disorder or other indications,
both psychiatric and non-psychiatric, should be
alerted about the need to monitor patients for
the emergence of agitation, irritability, as well
as the emergence of suicidality, and to report
such symptoms immediately to health care providers
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Unlike smallpox, depression has not been
disappeared since a cure became
availablePotentially fatal complications of any
treatment might be acceptable if the treated
population were small, dangerously ill, at high
riskthe availability of a remedy has increased
the diagnosis of depression a thousandfold.and
lethal side effects have increased by the same
multiplier.
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The drug manufacturers promote the
medicalization of stresssubsidize psychiatrists,
journals, conferences. Encourage moral
entrepreneurs of health whotalk about cases
undiagnosed, and so untreatedJohn Merson calls
this phenomenon epistemic capture the control
of knowledge by vested interests.
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200/100,000 represents 1 death in 500 people
treated with SSRIs in primary care.68/100,000 v
200/100,000A least 100 suicides per 100,000
over treatment with other drugs or non
treatment.By 2003, over 28 million people had
started Prozac since its launch in 1988.
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6,664,960 prescriptions for SSRI written 2003 by
Australian doctors.Twelve times the annual
number studied by Donovan40 of first
prescriptions remain unfinished, because of side
effects. PBS spends 160 million a year on
SSRIs.Cui Bono?
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I in 500 too rare for clinicians to see.They
need advice from suicide epidemiologists and
statisticians.Opinion evidence is not
admissible. We are not convinced and ad hominem
arguments do not get admitted as evidence. 1 in
500 is well above Rogers and Whittakers, 1
in 14,000 and demands a duty to warn of a
catastrophic side effect.
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Someone has that duty.Who will tell the
prescribing doctor? The manufacturers have not
done so in Austrlalia. The Therapeutic Goods
Administration has not issued warnings. The
Federal Drug Administration in USA argues that
its role is licensing drugs, not protecting the
public.Psychiatrists, all clinicians, are not
convinced.
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Some more alarming informataion has emerged from
David Healy's re evaluation of the clinical
trials of antipsychotic drugs presented to the
FDA.It concerns commonly prescribed
antipsychotic drugsThe regulator, the FDA,
just did not notice in the late 1980s that one in
208 or 12 in 2,500 clinical trial subjects
committed suicide while Zyprexa was being
trialled and only one on placebo and one on a
comparator, most likely haloperidol did that.
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SUICIDAL ACTS IN ANTIPSYCHOTIC TRIALS
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The subject numbers are so small that relative
risk cannot be calculated, but Zyprexa
(Olanzepine) trials had the highest rate of
suicide in clinical trial history. Suicidal
Acts have not been reportedRisperdal was not
far behind Zyprexa. The mechanism is thought to
be similar,through causing akathisia and doing
these drugs synergistically with SSRIs.
Doctors have not been warned.
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All Truth passes through Three Stages First, it
is Ridiculed...
Second, it
is Violently Opposed... Third, it is Accepted
as being Self-Evident.Arthur Schopenhauer
(1778-1860)
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In Friedsons account, moral entrepreneurs in
medicine are commonly part-time practitioners who
crusade in health matters. The thrust of their
activity is towards political power as they seek
to implement measures designed to improve what
they see as public health. They give press
interviews and try to give testimony in court.
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They are often responsible for legislation. They
want to place jurisdiction for their concerns in
the hands of health professionals rather than
leave them with society. Freidson identified
lay interest groups, sometimes led by, and always
including, prominent physicians, whom he
described as the most flamboyant moral
entrepreneurs of health, untrammelled by
professional dignity, crusading against the
menace of a specially chosen disease, impairment
or disease-producing agent
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Such moral entrepreneurs, essential players in
any moral panic, are ubiquitous. Professional
entrepreneurs are creating panics about the
consequences of child sexual abuse, others about
failing to have professionals attend immediately
on persons involved in traumatic events and about
depression which had become the greatest scourge
of modern society.
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They advert to cases of undiagnosed and
untreated post-traumatic stress disorder and
depression, which medication would surely cure.
They attribute to these evils a status of being
important causes of personal failure and
societys epidemic ills.
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Physician moral entrepreneurs are likely to see
the environment as more dangerous to health than
does the layman, and to emphasise the seriousness
of the health problem preoccupying them by
estimating the cases probably undiagnosed and
therefore untreated.
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They are disposed to see mental illness where
the layman sees nervousness, to see illness where
the layman sees variations within the broad range
of normality, to see a serious problem where the
layman sees only a minor one. They are biased
towards the creation of sick roles and press
their licence as physicians to manage the newly
defined sick within their relevant speciality
frameworks.
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In brief, the medical profession is more prone to
see illness and the need for treatment than it is
to see health and normality. This selective
perception is both self-confirming and
self-sustaining.