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History of the black box warning on antidepressants about "discontinuation syndrome"

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The first "black box" warning -- the U.S. FDA's most serious drug warning -- about the danger of antidepressant withdrawal syndrome was put on Paxil December 14, 2001, as a result of a class action lawsuit initiated August 19, 2000 in San Jose, California.
 
The site that described this lawsuit, http://www.capaxilclassaction.com/, has been closed; here is a snapshot of it as it appeared on 2 Jul 2012 https://archive.is/JCTOs (archived Web page) or https://www.mediafire.com/?dkjzru992htumvjhttps://www.mediafire.com/?dkjzru992htumvj (image of the page).
 
See http://usatoday30.usatoday.com/news/nation/2001/09/18/paxil-suit.htm or https://archive.is/dHujZ(archived Web page) or http://www.mediafire.com/view/3lqogt9a8ulp73i/091801-usatoday%20com%202016-06-03.png (image of the page).
 
(Status of Grair v. GlaxoSmithKline in 2012 http://www.law360.com/articles/334375/judge-asks-gsk-to-tweak-details-in-10-4m-paxil-settlement

(Testifying in this lawsuit is how Peter Breggin became famous, archived at https://archive.is/9H9Vk.)
 
From my correspondence with the FDA:

"Information on the Paxil discontinuation syndrome was added to the drug label on December 14, 2001. A direct link to the December 2001 label is provided below for your review: http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/20031s29lbl.pdf."
 
(Also stored at http://www.mediafire.com/download/sble3cbbbm3bxyh/121401_fda_black_box_paxil.pdf)
 
Here is the section added about withdrawal syndrome (deliberately called "discontinuation syndrome" by the drug companies because "withdrawal" suggested addiction):
 

Discontinuation of Treatment with Paxil: Recent clinical trials supporting the various approved indications for [/size]Paxil [/size]employed a taper phase regimen, rather than an abrupt discontinuation of treatment. The taper phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.
 
With this regimen in those studies,the following adverse events were reported at an incidence of 2% or greater for [/size]Paxil [/size]and were at least twice that reported for placebo: abnormal dreams (2.3% vs 0.5%), paresthesia (2.0% vs 0.4%), and dizziness (7.1% vs 1.5%). In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention.
 
During Paxil marketing, there have been spontaneous reports of similar adverse events, which may have no causal relationship to the drug, upon the discontinuation of Paxil (particularly when abrupt), including the following: dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), agitation, anxiety, nausea, and sweating. These events are generally self-limiting. Similar events have been reported for other selective serotonin reuptake inhibitors.

Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which [/size]Paxil [/size]is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE and ADMINISTRATION).


Following this, this article appeared 2002 Feb 2 in the British Medical Journal http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1122195/(Our topic here Tonks, 2002 Withdrawal from paroxetine can be severe, warns FDA) that was more straightforward:
 
 

GlaxoSmithKline, a leading drugs manufacturer, was last week forced to admit that paroxetine, a widely prescribed antidepressant and the company's best selling drug, can cause severe withdrawal symptoms when stopped.
 
The Food and Drug Administration in the United States published a new product warning about the drug, and in the same week the International Federation of Pharmaceutical Manufacturers Associations declared the company guilty of misleading the public about paroxetine on US television a year ago.
....
On 18 January the International Federation of Pharmaceutical Manufacturers Associations announced that GlaxoSmithKline had breached two of the industry's codes of practice.....
....
Dr Peter Haddad, consultant psychiatrist for Salford's Mental Health Service NHS Trust, welcomed the FDA's safety warning. He said: “Withdrawal side effects from antidepressants are far commoner than many people realise, and there's evidence that paroxetine has one of the highest rates. In most cases the symptoms are mild, but in a minority they are severe and prolonged—and treatable only by restarting the drug.”
 
There is also the danger of misdiagnosis and inappropriate investigation. Severe dizziness can easily look like labyrinthitis. Patients should be warned not to stop taking their antidepressants suddenly, and doctors should taper the dose at the end of treatment, keeping a close watch for withdrawal symptoms,” Dr Haddad added.
 
He also called for discontinuation problems to be thoroughly assessed before new antidepressant drugs are licensed. “This is a seriously under-researched area. There's no good evidence to help doctors get the dosing right as patients come off treatment. It's still a matter of trial and error.”

 
Despite the cautious language in the labeling on Paxil and generic paroxetine, there is cause to believe that all the drug's benefits have been exaggerated while risks hidden. It has been plagued by one scandal after another, revealing not only deceptive business practices but deceptive research practices, as in the notorious Paxil Study 329:

Le Noury, 2015 Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescents.
 
Eventually, in 2012, GlaxoSmithKline paid a record $3 billion in the US in fines for fraud allegations and failure to report safety data regarding Paxil, another antidepressant, Wellbutrin, and Avandia. Other governments also undertook disciplinary actions.

 

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Altostrata

While the Paxil discontinuation syndrome class action was wending its way through the U.S. courts, this paper appeared in 2001 in the journal Drugs & Therapy Perspectives. The author might be Dr. Peter Haddad.

 

"....while most antidepressant discontinuation reactions are mild and transient, others may persist for up to 3 months and/or be associated with substantial morbidity."
 
(The publisher could not identify the author of this article. It might be Peter Haddad.)

Drug Ther Perspect. 2001;17(20)
Antidepressant discontinuation syndromes: common, under-recognised and not always benign

from http://www.medscape.com/viewarticle/406547 Full text PDF here http://www.mediafire.com/download/qa5s4mh7m116eqk/01_drug_ther_not_always_benign.pdf

Introduction

Antidepressants have varying potentials to cause discontinuation syndromes. Symptoms begin within a few days of stopping or reducing the dosage of the drug and are usually mild and short-lived. However, in some patients, antidepressant discontinuation symptoms can produce significant morbidity, be incorrectly attributed to other causes, and lead to subsequent lack of compliance with antidepressant therapy. The best approach to the problem is prevention, which involves educating patients and healthcare professionals about discontinuation symptoms and ensuring that antidepressants are tapered before they are stopped. When symptoms do occur, reassurance is usually sufficient; in some patients, however, there may be a need for symptomatic treatment, temporary reinstatement of the antidepressant (followed by careful tapering), or a switch to fluoxetine (which has a low potential for discontinuation symptoms). More research into this common and clinically relevant syndrome is required so that evidence-based recommendations can be developed.

All Types of Antidepressants Are Implicated

So far, at least 21 different antidepressants have been reported to cause discontinuation symptoms. All major classes of antidepressants have been implicated.[1]

Many Different Syndromes Exist

Discontinuation syndromes vary considerably with respect to symptom type, grouping and severity. General features associated with discontinuation syndromes involving different classes of antidepressants are as follows:

  • In patients stopping selective serotonin reuptake inhibitors (SSRIs), the most common discontinuation syndrome involves 6 main symptom groups. Both physical and psychological symptoms may be experienced; the most commonly reported symptoms are dizziness, nausea, lethargy and headache[2]
  • As with SSRIs, tricyclic antidepressant (TCA)-associated discontinuation syndromes also include both physical and psychological symptoms but are much less likely to be associated with sensory abnormalities and problems with equilibrium. Hypomania, akathisia, parkinsonism, cardiac arrhythmias, panic attacks and delirium have been reported on rare occasions in patients discontinuing TCAs[1]
  • Stoppage of venlafaxine can result in an SSRI-like discontinuation syndrome[1]
  • Monoamine oxidase inhibitor (MAOI) discontinuation syndromes, particularly those involving tranylcypromine, can result in psychotic confusion, worsening of depressive symptoms, hypomania and generalised seizures.[1]
Key Clinical Features Suggest the Diagnosis

Common clinical features of antidepressant discontinuation syndromes include the following:
  • Antecedent antidepressant discontinuation or (less commonly) dosage reduction
  • Appropriate onset, i.e. usually within a few days of discontinuing or reducing the dose of an antidepressant
  • Adequate duration of treatment. Antidepressant discontinuation symptoms are rare in patients who have been treated for less than 5 weeks
  • Short duration (between 1 day and 3 weeks) if left untreated
  • Rapid reversibility (within 24 hours) on recommencement of the withdrawn drug.[1]
It is important to note, however, that while most antidepressant discontinuation reactions are mild and transient, others may persist for up to 3 months and/or be associated with substantial morbidity.[1]

Discontinuation Symptoms Common...

Discontinuation symptom rates in patients taking older antidepressants can be high, as evidenced by reports of 100% with imipramine, 80% with amitriptyline, 33% with clomipramine and 32% with phenelzine.[1] Abrupt discontinuation of treatment with newer agents such as sertraline,[3] paroxetine,[3,4] and venlafaxine[5] also results in spontaneously reported discontinuation symptoms in at least 1 out of 3 patients. Even higher rates have been documented when patients are specifically asked about symptoms, with one study finding evidence of discontinuation syndromes in 2 out of 3 patients treated with paroxetine and sertraline.[6]

...Except in Patients Taking Fluoxetine

Presumably because of the long half-lives of the parent drug (2 to 4 days) and its active metabolite norfluoxetine (7 to 15 days), fluoxetine appears to be much less likely to be associated with discontinuation symptoms than SSRIs such as paroxetine and sertraline.[1,7] When spontaneous adverse drug reaction reports in the UK (up to March 1993) were analysed, the rate of discontinuation reactions per 1000 prescriptions was 100 times lower with fluoxetine than with paroxetine (0.002 vs 0.3 per 1000, respectively) [see fig. 1].[8] Furthermore, in a double-blind placebo-controlled 'treatment interruption' study, discontinuation of fluoxetine for 5 to 8 days was found to produce fewer adverse events than discontinuation of sertraline or paroxetine for a similar length of time (p </= 0.001).[6]

Good History Makes Diagnosis Easier...

Unexpected physical or psychological symptoms in a patient who has recently stopped taking an antidepressant point to an antidepressant discontinuation syndrome. The diagnosis also becomes clearer when direct questioning reveals noncompliance with therapy in patients currently on an antidepressant prescription.[1]

...And Prevents the Pitfalls of Misdiagnosis

Antidepressant discontinuation symptoms can be misinterpreted as:[1]
  • Recurrence of depression in a patient who stops his/her antidepressant therapy following remission of the original illness
  • Evidence that an antidepressant is ineffective in a patient who fails to comply with his/her therapy
  • Adverse effects of a new antidepressant following switching from 1 antidepressant to another.
In all of these cases, subsequent decisions about investigation, referral and treatment are likely to be inappropriate, may lead to a waste of resources, and can contribute to an incorrect and more negative prognosis.[1]

Compliance May Suffer in Affected Patients

It is not uncommon for patients to miss antidepressant doses for several days. Such discontinuations would be expected to produce symptoms, which can develop within hours of missing a single dose of some agents. A compliance problem can then arise if the patient links his/her symptoms to the antidepressant without understanding the mechanism for development of symptoms, and particularly when the patient considers these symptoms to be evidence of 'addiction' to the antidepressant. In this way, discontinuation symptoms can result from, and cause, poor compliance.[1]

Tapering May Prevent Symptoms...

Various case reports have shown that discontinuation symptoms can be suppressed by re-introduction of the antidepressant, with subsequent tapering preventing their re-emergence. Such findings support the conventional recommendation that discontinuation of antidepressants should be tapered as a matter of routine.[1]

...But is More an Art Than a Science

Unfortunately, there are no controlled data demonstrating the effectiveness of tapering in general or of any tapering regimen in particular. According to the British National Formulary, antidepressants administered for 8 weeks or more should be reduced over a 4-week period.[9] Other authorities suggest reducing treatment dosage by one-quarter every 4 to 6 weeks after maintenance treatment. Another approach with SSRIs is to halve the dose and administer the drug on alternate days.[1]

A number of specific factors will also influence tapering strategies. These include:
  • The antidepressant used. Fluoxetine, for example, rarely causes discontinuation symptoms[6,8] and accordingly may not need to be tapered as a matter of routine.[6,8,10] Paroxetine[6,8] and venlafaxine,[5] in contrast, are much more likely to be associated with discontinuation symptoms and should therefore be tapered. Careful tapering is also required when stopping MAOIs, which can cause very severe discontinuation symptoms[1]
  • Duration of therapy. Discontinuation symptoms are more likely in patients who have received more prolonged periods of therapy. Indeed, there is probably no need for tapering in patients who have received antidepressants for short periods[1]
  • Previous history of discontinuation symptoms. Patients who have previously experienced discontinuation symptoms may require very gradual tapering.[1]
Fluoxetine May Help

Anecdotal reports suggest that fluoxetine, at least in some cases, can suppress discontinuation symptoms associated with other SSRIs and venlafaxine. When successful in this regard, fluoxetine can then generally be stopped without re-emergence of symptoms.[1]

Switching Therapies is a Special Case

The importance of establishing effective antidepressant therapy overrides concerns about possible discontinuation symptoms in patients who require a switch of antidepressant therapy because of lack of efficacy. In such cases, rapid tapering or even abrupt switching is often justifiable, although the potential for discontinuation symptoms must be borne in mind. Other factors to consider when switching antidepressants include the possibility of drug interactions and the need for an appropriate wash-out period.[1]

Education of Both Patients and Doctors Needed

Current evidence suggests that substantial proportions of general practitioners, psychiatrists and pharmacists are unfamiliar with antidepressant discontinuation syndromes. In addition, patients are generally unaware that antidepressants are not addictive, that abrupt stoppage of antidepressants (because of noncompliance or when starting drug holidays to reduce adverse effects) can cause discontinuation symptoms, and that tapering of antidepressants is recommended to avoid such symptoms.[1]

Flexible Approach to Treatment Required

Patients with discontinuation symptoms who remain depressed (e.g. treatment noncompliers) and those who are at high risk of relapse/recurrence should be recommenced on their antidepressant. In other cases, the severity of the discontinuation syndrome should determine treatment. Most patients will have mild reactions and need to be reassured only. Symptoms of moderate severity may require symptomatic treatment (e.g. short course benzodiazepines for insomnia). Severe or treatment-refractory symptoms may require recommencement of the antidepressant and subsequent careful tapering. Antipsychotics and hospital admission may also be required in patients who develop severe mania, confusion or psychotic symptoms.[1]

Newborns Can Develop Symptoms...

Maternal use of antidepressants during pregnancy can result in a neonatal discontinuation syndrome characterised by symptoms such as irritability, respiratory difficulty and poor feeding. Tapering or discontinuing antidepressants prior to delivery may therefore be beneficial for the neonate, but also introduces the risk of depressive relapse in the mother. Neonates born to mothers on antidepressant therapy should be monitored for discontinuation symptoms over the first week of life.[1]

...Or Even as a Result of Breast Feeding

All antidepressants studied have been shown to be present in breast milk and therefore have the potential to cause toxic effects in breast fed infants. Furthermore, a possible case of neonatal discontinuation reaction following abrupt discontinuation of sertraline by a nursing mother has been reported.[11] Whether the possibility of antidepressant neonatal toxicity and/or discontinuation symptoms outweighs the benefits of breast feeding for mother and infant is a decision which can be made only on a case by case basis.

References

1.Haddad PM. Antidepressant discontinuation syndromes: clinical relevance, prevention and management. Drug Saf 2001; 24 (3): 183-97

2.Haddad P. The SSRI discontinuation syndrome. J Psychopharmacol 1998; 12 (3): 305-13

3.Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment: double-blind, placebo controlled trial. Br J Psychiatry 2000; 176: 363-8

4.Oehrberg S, Christiansen PE, Behnke K, et al. Paroxetine in the treatment of panic disorder: a randomised, double-blind, placebo-controlled study. Br J Psychiatry 1991; 167: 374-9

5.Fava M, Mulroy R, Alpert J, et al. Emergence of adverse effects following discontinuation of treatment with extended-release venlafaxine. Am J Psychiatry 1997; 154 (12): 1760-2

6.Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomised clinical trial. Biol Psychiatry 1998; 44: 77-87

7.Olver JS, Burrows GD, Norman TR. Discontinuation syndromes with selective serotonin reuptake inhibitors: are there clinically relevant differences? CNS Drugs 1999 Sep; 12 (3): 171-7

8.Price JS, Waller PC, Wood SM, et al. A comparison of the postmarketing safety of four selective serotonin re-uptake inhibitors, including the investigation of symptoms occurring, on withdrawal. Br J Clin Pharmacol 1996; 42: 757-63

9.British National Formulary. No. 41. London: The Pharmaceutical Press, 2001 Mar: 187

10.Rosenbaum JF, Zajecka J. Clinical management of antidepressant discontinuation. J Clin Psychiatry 1997; 58 Suppl. 7: 37-40

11.Kent LSW, Laidlaw JDD. Suspected congenital sertraline dependence [letter]. Br J Psychiatry 1995; 167: 412-3


Original at Drugs & Therapy Perspectives:
8 October 2001 - Volume 17 - Issue 20 - pp 12-15
Drug Reactions and Interactions

Drug Ther Perspect 17(20):12-15, 2001

 

 
 

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Altostrata

Following the inclusion of a "black box" warning for discontinuation syndrome on Paxil, the FDA began to require it on other new antidepressants.
 
(The danger of withdrawal syndrome for the older tricyclic and monoamine oxidase inhibitor antidepressants was well known, for example:
Hodding, 1980 Drug Withdrawal Syndromes: A Literature Review

Dilsaver, 1984 Antidepressant withdrawal phenomena. )

 

For example, Lexapro was approved by the FDA in 2002. In 2004, the approved labeling included the black box warning for discontinuation syndrome:

 

Discontinuation of Treatment with LEXAPRO During  marketing  of  Lexapro  and  other  SSRIs  and  SNRIs   (serotonin  and  norepinephrine  reuptake  inhibitors),   there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly  when abrupt, including the following:  dysphoric  mood, irritability, agitation , dizziness, sensory  disturbances (e.g.,  paresthesias  such  as  electric  shock  sensations),  anxiety,  confusion,  headache,  lethargy,  emotional  lability,   insomnia,  and  hypomania.  While  these  events  are  genera lly  self-limiting,  there  have  been  reports  of  serious   discontinuation symptoms. 

 

Patients  should  be  monitored  for  these  symptoms  wh en  discontinuing  treatment  with  LEXAPRO.  A  gradual   reduction  in  the  dose  rather  than  abrupt  cessation  is  recommended  whenever  possible.  If  intolerable  symptoms   occur  following  a  decrease  in  the  dose  or  upon  disc ontinuation  of  treatment,  then  resuming  the  previously   prescribed dose may be considered. Subsequently, the phys ician may continue decreasing the dose but at a more  gradual rate.

 

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Altostrata

Subsequently, almost all psychiatric drugs put on the market since 2004 are labeled with warnings against abrupt discontinuation and similar instructions to the physician to monitor for withdrawal symptoms and reinstate the drug should withdrawal symptoms appear.
 
Very few doctors are aware of these warnings and instructions. Almost always, they will misdiagnose withdrawal symptoms as "relapse" or emergence of a new psychiatric condition, often some variety of "bipolar disorder."
 
See

Haddad, 2000 Misdiagnosis of antidepressant discontinuation syndrome

Re: Depression, Stroke Diagnosis, and SSRI Discontinuation Syndrome

Warner, 2006 Antidepressant discontinuation syndrome
 
1 Boring Old Man » high index of suspicion…
 
Muzina, 2010 Discontinuing an antidepressant? Tapering tips...

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nz11

Thanks for posting this.

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nz11
see : 2 July 2012 https://archive.is/JCTOs (archived Web page)

GSK must have been laughing with this part of the settlement ...giving them another marketing opportunity for pushing druggery guidelines set up and hijacked by themselves....

 

"The settlement also provides that GSK shall also make a charitable contribution in the total amount of $1,000,000.00 to the following organizations: (1) Mental Health America in California; (2) National Alliance on Mental Illness; (3) American Foundation for Suicide Prevention; and (4) DiDi Hirsch Mental Health Services, with a direction that the contribution be used for the provision of mental health services, including psychiatry and case management, and mental health training and education in the State of California. Each organization shall receive a donation of $250,000.00."

 

Nothing like promoting your cause !

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Altostrata

The drug companies were alarmed by reports of withdrawal syndrome from SSRIs such as Prozac in the early '90s, and the warning labels they now had to put on their antidepressants.

 

To control the potentially negative effects on drug sales, they convened two "expert consensus panels" to lay down guideline for psychiatry:

Schatzberg, 1997 Serotonin reuptake inhibitor discontinuation syndrome.... sponsored by Eli Lllly, manufacturer of Prozac.

 

Schatzberg, 2006 Antidepressant discontinuation syndrome: consensus panel recommendations... sponsored by Wyeth, manufacturer of Effexor.

 

Both multi-author publications were published as "supplements" to The Journal of Clinical Psychiatry, the official journal of the American Society for Clinical Psychopharmacology. "Supplements" are paid advertising sections that look like part of the journal.

 

Both publications portrayed antidepressant withdrawal syndrome as mostly mild and transitory. This has been read by doctors as always mild and transitory.

 

The 2006 publication states that any symptomology lasting beyond a few weeks is not withdrawal syndrome but "something else." At the time it was published, the author of that statement, Richard Shelton, wrote me the attached e-mail confirming the existence of prolonged withdrawal syndrome Shelton, 2006 Correspondence from Dr. Richard Shelton about prolonged withdrawal syndrome

 

Dr. Shelton, like most of the members of the two "expert consensus panels" went on to very lucrative relationships with pharmaceutical companies.

 

The exception is Peter Haddad, a British psychiatrist who is a relatively independent expert in psychiatric drug adverse effects Haddad, 2004 Adverse Syndromes and Psychiatric Drugs: A Clinical Guide

 

In a 2001 paper, Dr. Haddad wrote: "Most reactions are mild and short-lived and require no treatment other than patient reassurance. Severe cases can be treated symptomatically or the antidepressant can be reinstated before being gradually withdrawn. Reinstatement usually leads to symptom resolution within 24 hours. Some individuals require very conservative tapering schedules to prevent the re-emergence of symptoms."

Author or co-author of many papers about antidepressant withdrawal, Dr. Haddad is always careful to say "usually" or "most" when it comes to sunny predictions about how long withdrawal syndrome takes to resolve, because he knows there are cases where it takes many months or even years to resolve.
 

Those reports of severe antidepressant withdrawal syndrome are unpublished and have been buried by the pharmaceutical companies, but researchers such as Haddad, Alan Schatzberg, and Richard Shelton are well aware of them.

Haddad goes on to say: "Discontinuation symptoms have received little systematic study with the result that most of the recommendations made here are based on anecdotal data or expert opinion. Research is needed to provide a firm evidence base for future recommendations."

In short, whatever medicine knows about antidepressant withdrawal syndrome is based on anecdotes collected by a few researchers, their opinions shared over filet mignon dinners bought by Lilly and Wyeth, filtered through drug company interests, and recycled throughout the entire body of literature on the subject.

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SunnySkies

Not one single doctor has warned me, or informed me of any withdrawl effects when I started this medication.

 

 

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