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2001 Antidepressant discontinuation syndromes: common, under-recognised and not always benign

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Altostrata

"....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

Edited by Altostrata
updated

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btdt

I have to take issue with this:

Fluoxetine May Help

Myself and others can attest to the horrid withdrawal reaction of Fluoxetine (Prozac) the withdrawal is different not as fast to hit but in my experience it is longer and very disabling. It is not the answer many wish it were. The answer is not to take these drugs in the first place and force the powers that be to find what is actually going on in stead of guessing. Anyone thinking of take Prozac to help with withdrawal should read the book Let Them Eat Prozac and the Prozac Backlash.

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Altostrata

I would say that using fluoxetine (Prozac) to treat withdrawal would be a two-edged sword.

 

Yes, fluoxetine has withdrawal issues itself. But if you just can't get off Effexor, Paxil, or Cymbalta, the risk may be worth it.

 

At the worst, you'd be trading a horrible withdrawal from Effexor, Paxil, or Cymbalta for a horrible withdrawal from fluoxetine.

 

Fluoxetine truly has a better track record for withdrawal than the other antidepressants. Not perfect, but better.

 

And there are reports that doctors have successfully switched patients to fluoxetine to get them off the other antidepressants. How likely is that? No one knows.

 

So, again, you pays your money and you takes your choice. Guidelines are few.

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btdt

I would like to add as a side note that it was after my brief contact with Prozac that I became chronically unwell with pain in areas I had not felt or hurt previously. Indeed when I went into a pain clinic after a long time in ct withdrawal by myself I was diagnosed with fibro given the Amitriptyline for pain it helped a lot. I cannot help but wonder was it treating withdrawal? Of course at the time I didn't even know I was on an antidepressant with the prozac that is the other was well explained to me I stay at a low dose of 10mg for pain control but had to take it at six by seven I could not see the tv my eyes were so blurred.

Interesting too is the article I found saying serotonin syndrome was misdiangnosed as fibro on we go be it here a piece there it is a puzzle.

My fear maybe uncalled for but it is that prozac has a special penchant for causing fibro of course this may be totally unfounded.

It was around 2 year between the prozac less than a month of it to the pain clinic... so that is along time the majority of it spent in pain and sleepless. Before going to the clinic I had to watch my activity and fill in questions... to my own surprise I was upright about 2hours a day the rest I was sitting or laying down tho I could not sleep insomnia was a huge issue. K that is all I know about prozac I think withdrawal from it lasts a long long time.

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Altostrata

Yep, switching to Prozac has its own risks.

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Rhiannon

Yep, switching to Prozac has its own risks.

 

Also want to mention that Prozac has a strong history of causing akathisia. In fact, when Eli Lilly first was trying to get it approved by the FDA, they couldn't because of the akathisia it caused, which was worsening peoples' symptoms in the studies they were conducting. How did they get around it? By giving the study subjects Xanax.

 

So what really got approved was the combination of Prozac and Xanax. Not stated as such, of course. (And yes, this IS science fraud, if you were wondering.)

 

And this is the combination that started me down my personal Yellow Brick Road to Hell.

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btdt

 

5 Days Ago (Day 7 of (almost) no drugs) I Took a small three ~15 mg doses when discontinuation symptoms became intolerable.

 

Last few days I experienced (as expected) progressively worse discontinuation symptoms

 

1 Day Ago (yesterday) The discontiantion symptoms were very bad yesterday afternoon but I was out and about with no access to meds so I had to push through it. By the time I got home in the evening the crisis had passed and I've felt progressively better since. I realise that this goes against the tapering recommendations on this site (and just about everywhere else), but since I have arrived where I am rather unintentionally (if a little neglectfully) I am thinking of continuing to wait and see what happens.

 

QUESTION: If I am going to develop chronic brain disturbance by stopping so abruptly (and so should continue on a more conventional, gradual taper as recommended on this site to prevent this damage), would I have phsyical and mental sensations which would indicate this? Will I continue to improve each day adn then one day start getting symptoms fo this kind of damage? Or is it experienced as a discontinuation symdrome that never eases up?

 

I have not taken this particular drug but I have tried a few antidepressants.

Some people have no withdrawal I don't know them.

Anybody can quit taking any antidepressant there is no trick to it I did it cold turkey. I felt not too bad quitting Effexor like this till the sixth wk.. ok it was no walk in the park but I was already in tolerance so was sick anyway things were a bit tricky till the sixth wk. In the 6th wk I got what I thought was the flu I was in bed 3months the next 3 were not much better... two months later at 8 months off I found ****** and started learning about withdrawal and tapering. I wish I had known sooner but I didn't.

My life fell completely apart and I have not been able to restart or regain those losses. I am for sure better at 3.5 years post cold turkey but really do you want to destroy your life...

Withdrawal is a crap shoot some apparently don't get it.

You are at least further ahead than I in that you know there is such a thing as withdrawal you can keep going as you are and if....in my opinion when you get into trouble you can go back up in dose wait to get stable then start your taper or you can get on to the tapering now. If you have to get back on later it may take some time to work and in the long run you will save yourself some time and likely much suffering if you just taper now. It is your choice however and maybe you will get lucky. You are not alone in wanting to see if you are one of the lucky ones many have tried it. I don't know if you are going to have a bad time or not neither does anyone else.

I can tell you getting off an antidepressant is doable I have done it 5 times all cold turkey but I always was back on another ad soon after.. had no idea I was treating withdrawal as I didn't know there was such a thing. I think if you want to get off and stay of antidepressants and have a life while you are getting off the smart way to do it is to taper.

Now I will tell you why.

When you increase the serotonin in your brain your brain see this as an imbalance so it stops making as much serotonin and it shuts down some receptors ...two ways your body has to reduce serotonin. You body acts slowly unlike the drugs and this can take a very long time.

When you quit cold turkey + your body has reduced serotonin = low serotonin

You now have really low serotonin maybe for the first time in your life this is what I think causes severe withdrawal effects. It takes your body a long time to catch up make more serotonin and grow or otherwise rebuild receptor activity... I am sure having this abrupt change hampers your bodies ability to get up to speed as it has to recover from the shock of no serotonin.... and then start the repair process.

If you taper you body can adjust slowly to upregulating serotonin and does not have to take time to repair from the shock of ct.

that is my take on it I know other people on here know all about this and could likely explain it better I am trying to keep it simple. good luck

nobody can predict what will happen as we hear all the time some people don't have withdrawal the people we see on boards like this are not those people but if you do ct you are more likely to have protracted withdrawal which means last a long time plus the withdrawal will be much more severe ...more suffering

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btdt

 

Yep, switching to Prozac has its own risks.

 

Also want to mention that Prozac has a strong history of causing akathisia. In fact, when Eli Lilly first was trying to get it approved by the FDA, they couldn't because of the akathisia it caused, which was worsening peoples' symptoms in the studies they were conducting. How did they get around it? By giving the study subjects Xanax.

 

So what really got approved was the combination of Prozac and Xanax. Not stated as such, of course. (And yes, this IS science fraud, if you were wondering.)

 

And this is the combination that started me down my personal Yellow Brick Road to Hell.

 

I am curious Rhi how long did you take prozac? why did you quit when you did?

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Altostrata

I was unable to find the author of the above article in Drugs & Therapy Perspectives 8 October 2001 - Volume 17 - Issue 20 - pp 12-15 but I believe it is Peter Haddad.

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