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Cette page est traduite de l'excellent  site du Dr Phelps (Oregon USA) dont l'indépendance du ton et des jugements est remarquable ( la page de titre est rappelée ci-dessus).

Antidépresseurs dans les troubles Bipolaires: Les Controverses
(revised 9/2004)

Controverse 1:   Fréquence du switch.  Les Antidepresseurs (AD) peuvent causer un  "switch", une bascule de l'humeur de la depression à l'hypomanie ou à la manie, mais quelle est la fréquence de ce phénoméne? Peut-on identifier par avances les "switchers"? Les thymorégulateurs protégent-ils contre cela? 

Controverse 2:   "Déstabilisation de l'humeur":   Un risque à long-terme existe-t-il derrière le risque de "switch" à court terme ?

Controverse 2a: "Kindling" (abaissement du seuil de déclenchement d'un épisode): Les AD peuvent-ils être la cause d'une aggravation à terme d'un trouble bipolaire ?  (Personne, en dehors de moi [J;Phelps] -- ou peut-être de quelques autres extrémistes -- n'apparait avoir peur de cela). 

Controverse 3: AD au long cours. Pour les patients  déjà sous AD et qui sortent d'un épisode dépressif, doivent-ils arrêter ce traitement ou le continuer ? 

Controverse 1  Fréquence de la bascule de l'humeur.

Quelle est la fréquence de développement d'hypomanie ou de manie d'un patient déprimé bipolaire, à qui l'on donne un  antidepresseur ? (un phénoméne dénommé  "switching" ou bascule de l'état dépressif vers l'état hypo/maniaque). 

 There are two large and recent reviews of this issue.  In Sept 2004, Gijsman and colleagues reviewed 12 randomized trials in which patients (75% of whom were already on a mood stabilizer of some sort) were given antidepressants or placebo.  The switch rate in this meta-analysis was no greater in those given an antidepressant than those given placebo; and the antidepressants were more effective than placebo.  So, does this study put the issue to rest?  

From the online abstract (journal issue itself not out yet; I'll revise this when it is), it's clear the authors are emphasizing "short term risk" of switching, so the follow-up periods will be of interest.  And the definition they used for "switch" will be important.  However, it is considerably more reassuring than the literature to date, e.g. a review of this same question by Goldman and Truman (Dec. 2003), whose extensive report summarizes a complex  literature.  They conclude that "switch rates" generally vary from 20% to 40%, which is difficult to reconcile with this new report from Gijsman et al.  Goldman's review showed that mood stabilizers do not clearly prevent this problem, but they may diminish it, which may account in part for the different switch rate conclusions.  Again, Goldman and Truman reviewed an extensive literature, whereas Gijsman et al looked only at randomized trial data.  You statistical sophisticates will want to note a recent commentary which holds that observational data, such as a recent retrospective review which showed a switch rate of 49%^Ghaemi, are more accurate for assessing the frequency of such effects than randomized trials. 

Dans le traitement d'attaque de la dépression, la question doit être posée différemment comme indiquée ci-dessous.  Il est clair que pour les  Bipolar I, les  antidepresseurs peuvent entraîner des symptômes de manie; il est moins clair avec quelle fréquence ces médicaments peuvent induire une hypomanie pour les  Bipolar II, et beaucoup plus difficile de mesures les  "switch rates" ou "taux de bascule".  

Le "point de transition" -- le point où l'AD commence à entrainer des risques d' hypomanie -- est-il mieux indiqué par la fléche jaune ou par la fléche verte ci-dessous? 

Pour les patients en attente de leur premier traitement pour dépression et qui peuvent se tromper sur leur place dans le spectre bipolaire, c'est une question cruciale : ou est la bonne fléche ?  Cependant, nous n'avons aucun critére pour positionner un patient dans le spectre, même si nous pensons ou la fléche doit se situer.  (Le point le plus proche pour la "position" d'une personne donnée est celle attribuée par le questionnaire papier/crayon nommé  Bipolar Spectrum Diagnostic Scale).  Presque tous les psychiatres sont d'accord sur le principe : pas d'AD si le patient est à droite de la fléche.  Nous [les psychiatres] sommes juste en désaccord sur la position de la fléche.!

(Two new developments, as of 9/2004: first, here's a clinician who suggests using insomnia as a marker for patients to treat with mood stabilizers -- not hypomania or even any manic-side symptoms, just insomnia!^Boyle  It's nice to see someone suggest something so radical that it strikes even me as "too out there".  Deuxiémement un groupe de recherche bien connu sur les troubles de l'humeur suggére d'abandonner le concept de "spectre bipolaire" en faveur d'une conception unitaire regroupant la depression unipolaire et le spectre bipolaire comme une seule entité avec différentes manifestations. Il y a un graphique intéressant dans  un remarquable rapport).  

Nous avons juste quelques données où les différents psychiatres situent la fléche, métaphoriquement parlant : 

Il apparait que plus un psychiatre est centré sur une clientéle de patients bipolaires et plus il/elle emploie les antidepresseurs avec mesure.  L'auteur de ce rapport  reconnait que pas plus de 20-40% de ses patients avec des troubles bipolaires reçoit des AD,  plûtot que les 80% de patients des psychiatres non spécialisés.^Ghaemi  

The dilemma as to whether to give an antidepressant to someone who might have an undetected, underlying bipolar disorder, is even worse in children, of course.  Recently an entire issue of the main Child/Adolescent psych' journal was devoted to this  switching issue, all of which is available in full text.   See the masterful  summary editorial by Gabrielle Carlson, entitled "The Bottom Line".    Then see a review of how complicated it can be sorting out rapid cycling from continuous symptoms, with or without antidepressants, by Dimitri Papalos.  At the bottom is research led by Melissa DelBello which suggests that at least in the first 1-2 years after exposure to antidepressants, in depressed kids at high risk for bipolar disorder, there is no increase in "switching" into mania -- perhaps even a protective effect!

An emerging view is that the risk of antidepressant-induced switching into hypo/mania varies depending on the patient.  Risk factors include hyperthymic temperament ^Henry; as well as multiple previous antidepressants, female gender, and thyroid abnormalities.^Pies  For more details on these factors, including conflicting data about the "female gender" factor, see an excellent review by Drs. Goldberg and Truman.  They note that patients in their Cornell Bipolar Cohort who "switched" while taking an antidepressant had had more antidepressant trials per year than those who did not switch.  This could be interpreted as one more tiny bit of evidence supporting the idea that antidepressant exposure, in the long-term, might carry some risk in bipolar disorder.  For example, it might make a person more "switch prone".  That matches my experience with patients.  People who have had a lot of antidepressants seem "touchier" in terms of what it takes to destabilize them.  Of course, they could have had a "touchier" illness in the first place, and that was why they got all those antidepressants! 

En conclusion de cette première controverse, nous devons reconnaitre qu'il y a un long chemin à parcourir avant que nous connaissions exactement quels risques les anti-dépresseurs entraînent, dans le court terme et à quelles populations.  Cependant, il ne fait pas de doute qu'il y a des risques. Même la FDA impose maintenant (en utilisant le conditionnel  Mise en garde FDA) aux docteurs de parler aux patients des risques de bacule maniaque et autres symptômes bipolaires.  Maintenant regardons les riques à long terme des AD.

Controverse 2:  Déstabilisation de l'humeur.

les AD peuvent entraîner une accélération des épisodes (le cycle) et la nécessité de prendre plus de médicaments pour prévenir les cycles. Cela a été nommé "Déstabilisation de l'humeur". Les préocuppations autour du "switch" souvent entraînent plus d'emphase sur le devenir à long terme du trouble. Dans mon expérience, les médecins ne se posent pas souvent la question. Cependant les études suggérent que le risque est réél.  

In fact, one of the world's experts on this subject believes this very strongly.  Dr. Nassir Ghaemi, a Harvard assistant professor and head of the Bipolar Disorder Research Program at Cambridge Hospital, recently guest-edited a review of the risks of antidepressants in bipolar disorder, to which an entire issue of the journal Bipolar Disorder was devoted (Dec. 2003).   His co-authors include some of the best-known bipolar experts.  He clearly has a "big picture" view spanning years of mood disorder research that can be used to examine this issue.  In other words, this guy is not an extremist. He represents a keep-the-risks-down, thoroughly data-based viewpoint. 

His review, with Drs. Hsu, Soldani, and F. Goodwin, entitled  "Antidepressants in Bipolar Disorder: the case for caution"²⁰⁰³ , is worth reading for anyone who thinks we've all gone a little too anti-antidepressant.  Their article was structured as a response to a nearly opposite point of view, from an earlier European essay.^Moller  A more recent view similar to the Europeans'  was presented by Dr. Altshuler in a Point/Counterpoint pair of essays ^** where again Dr. Ghaemi was selected to present a short version of his 2003 cautionary review.  Below you'll find a summary table from that 2003 article.  I hope the summary makes you just itch to see the data they each cite as the basis for the assumptions and conclusions, which obviously differ considerably.  If you're able to do so, you will find that the Ghaemi group citations span a broader range of the available literature, both in time and scope.  

In my travels it appears that the Altshuler point of view is more common amongst community psychiatrists --  which matches the data above on the frequency of antidepressant use in bipolar disorder.  Since this difference in practice seems ultimately to lie in different interpretations of the risk data, not in different value systems (e.g. how much risk we're willing to expose patients to), I'll offer one more data set which I find particularly telling.  Dr. Ghaemi's essay also highlights this study, from back in 1988^Wehr:  

Each color represents a different patient's cycle lengths (note that's in days -- we're watching multiple cycles over a period of many, many months here) These folks are not your average person with bipolar disorder.  They were at the NIMH for research and were "treatment-resistant" to be sure, highly selected, and further selected for antidepressant-induced cycling by the design of this study.  But the important result here is to recognize a clear reduction in cycle length when the patients went onto an antidepressant (a TCA) in addition to their ongoing lithium.  Think about it:  a reduction in cycle length.  We're not talking about switching here, we're talking about changing the course of bipolar disorder, at least while they're on an antidepressant.  Not just one switch, but more switches than they would have had were they not on the antidepressant.  

This leads to the other major point stressed by Drs. Ghaemi and colleagues:  there is no good (randomized, blinded trial) evidence for sustained mood benefit from going on an antidepressant, versus management with mood stabilizers. And remember, the latter strategy will not cause short or long-term destabilization.  Here is a slightly paraphrased summary from Ghaemi et al's review of the two existing studies of this issue:  

In a large study, the addition of an antidepressant (paroxetine or imipramine) to lithium was not more effective than lithium-plus-placebo -- at least in patients with therapeutic lithium levels (> 0.8 ng/dL).^Nemeroff  In another smaller (but randomized and blinded) study, the addition of paroxetine to a mood stabilizer (lithium or valproate) was not more effective than the continuation of two mood stabilizers.  Although the two-mood-stabilizer group experienced more side effects, because full doses of each stabilizer were used, adding paroxetine instead of an additional mood stabilizer did not produce a better outcome in terms of mood.^Young  (It should be acknowledged, however, that in the latter study, a true difference could have been missed because of the small sample size). 

There is no doubt that antidepressants can treat depressive symptoms in bipolar disorder.  The issue is whether they do it better than mood stabilizers alone.  And there should be some good evidence to that effect, because we know that they carry more risk of worsening the condition.   

En conclusion de cette seconde controverse, à mon avis (qui recoupe les  recommendations de Ghaemi et al ci-dessus, il est de bonne pratique de restreindre l'usage des AD aux cas suivants :

      The patient is already on a mood stabilizer with antidepressant effects (lithium, lamotrigine, perhaps even fish oil; or perhaps Zyprexa, Seroquel, or risperidone -- which may not be "mood stabilizers" in the purest long-term sense, we don't know yet, but all of which have data supporting their antidepressant potential); and

1. for some reason, adding another medication from the above list is not a good idea; and
2. she/he is still very depressed, with no evidence of slow improvement; and
3. her/his depression has no clear features of hypo/mania or instability.  In other words: 

• she is sleeping too much, or at least without repeated interruptions or too little total sleep; and
• he shows very low energy, not too much, such as agitation or anxiety; and
• she is "stably depressed", with no evidence for rapid cycling; and
• there is no clear history of antidepressant-worsening of cycling.  And, 
• there is no mood lability, a strange reaction where tears or anger or laughter are extremely easily provoked, such as by a TV commercial or poor driver or bad joke.  

Controverse 2a: "Kindling" 

Les antidepresseurs peuvent-ils causer le "kindling"?  Le mot "kindling" est originaire de la neurologie, où il a été employé pour décrire des formes d'épilepsie qui s'aggravent avec le temps.  Dans ce modèle,  chaque épisode de la maladie rend les épisodes ultérieurs plus proches et plus sévéres. Il est clair que quelques patients bipolaire ont, avec le temps, des épisodes plus frequents et plus sévéres. Cette évolution peut-t-elle être déclenchée par les antidepresseurs, au moins pour quelques patients prédisposés ?   

Voici un bon exemple visuel du phénoméne dont nous parlons.  Le graphe ci-dessous montre les épisodes d'humeur d'un homme dont les troubles bipolaires semblent clairement s'aggraver avec le temps (son âge est montré en dessous, le rouge montre les durées d'hospitalisations, avec les épisodes maniaques en-dessus de la ligne et les épisodes dépressifs en dessous, of course): 

Note the pattern:  after each episode, the next episodes come sooner and are more severe.  This is the "kindling" pattern, though this man's experience alone of course does not prove that the illness itself can do this.  There could have been some other factors, such as alcohol or other drugs, etc. 

However, suppose some forms of bipolar disorder really do "kindle" themselves.  If that is so, then any worsening has the potential to be a "permanent" worsening.  In the graph above, time only moves to the right.  If a patient gets "jumped" further to the right, by having an episode triggered, that could represent a permanent worsening.  She could reach a point at age 35 that otherwise might not have been reached until age 40, you see?  If this illness truly worsens with each episode, then causing an episode by using something like a lot of alcohol -- or perhaps an antidepressant? -- is like "speeding up time".   This could make the illness harder to control, requiring more medications than it otherwise might have needed.    

This "kindling" concern is very rarely raised in the bipolar literature, at least as regards antidepressants.  One of its early proponents, Dr. Robert Post of the NIMH, is still describing this phenomenon in terms akin to epilepsy;^Post but he is not as concerned about antidepressants as some.^Post(b)  However, the logic still seems compelling to me, as a possible, plausible risk.  We will not likely know if this is true until the molecular basis of bipolar disorder is better understood, so we can look for a biological marker to follow -- because there are so many variables which can affect the course of a person's bipolar disorder, it is hard to know whether the antidepressant might have been the "causative" one, over many years time.  For now, this possible, plausible risk is just one more reason, in my opinion, in addition to those above, to avoid using antidepressants where possible.  

Controverse 3:  AD au long cours. Votre patient va mieux (et prend un thymorégulateur).  Maintenant doit-on continuer ou arrêter l'antidepresseur?  

This got a lot more complicated as of July 2003 when Dr. Lori Altshuler and colleagues^Altshuler published a study showing that antidepressants, when continued along with a mood stabilizer, were associated with a substantially better outcome than when they were tapered early.  This is somewhat counter to the usual recommendations, e.g. as I had heard 2-3 years ago from Dr. Sachs of Harvard, and others.  At that time they recommended discontinuing antidepressants in patients with bipolar disorder much earlier than we would usually do in unipolar depression.  Dr. Altshuler and colleagues' paper has brought that recommendation into question, so that now there is no clear recommendation on how long to continue an effective antidepressant used in conjunction with a mood stabilizer.  

However, despite how frequently it is cited, the Altshuler et al report was not a randomized trial (it may appear so from the graph unless one looks closely).  Many patients were screened out before arriving at the final results, far more than were followed through the reporting period.  Here is a breakdown of the structure and results of  the Altshuler study.  It is amazing how often this study is cited, and how firmly, given the way it is structured (a naturalistic follow-up of a select group of patients).  Unfortunately these results are almost all we have to go on right now, on this question.  And they clearly do suggest that for patients who have done well for many months on antidepressants (with a mood stabilizer), it may be best to leave them on the antidepressant.   

En conclusion pour cette troisième controverse   pour un patient qui va bien, euthymique ou presque (sans symptômes), soit laisser le patient sur son AD ou suggérer un très lent sevrage (sur au moins plusieurs mois) sont aisément justifiables sur la base des données actuelles. S'il y a quelque symptôme de manie que ce soit, la plupart des experts sont d'avis que le sevrage des AD doit améliorer le cours du trouble bipolaire à long terme.

EN RESUME (mes opinions): 

1. N'employez pas d'AD si l'hypomanie est clairement présente.

2. Si le patient devient hypomaniaque quand on lui donne un AD, impérativement considérer un thymorégulateur (voir guidelines sur leur usage en soins primaires) comme opposé à un autre essai d'antidepresseur..

3. Dans le doute, demander une consultation de diagnostic(si aucun psychiatre n'est disponible, utilisez un docteur dont vous avez confiance dans le diagnostic) avant de commencer le traitement.  Au minimum, employez le test  1-page screening tool to "rule out bipolar", et/ou faites lire à votre patient le texte read about bipolar II  pour encourager ses pour préciser le diagnostic en toutes connaissance des risques..

Important Article Links

• Best single review, presenting two somewhat opposing points of view:  Drs. Lori Altshuler and Nassir Ghaemi, "Point/Counterpoint" format (make sure to scroll down past her article to read his).  

Articles/Experts Suggesting Use Caution

• Looking back at records for bipolar patients placed on antidepressants while on mood stabilizers, in a recent review of 20 studies of rapid cycling^Kupka , 46% of the patients seemed to have their rapid cycling begin after an antidepressant, though the authors emphasize that a "causal" effect was not established.  

• Ghaemi N:
  See a series of essays by Dr. Ghaemi on this subject, all of which echo main themes on this website: 

  • Is Bipolar Disorder Misdiagnosed?
  • Antidepressants and Bipolar Depression: First, Do No Harm
  • Antidepressants in Bipolar Disorder: Are They Safe? Are They Effective?
  • The Bipolar Spectrum: A Valid Forme Fruste?
  • Mixed states: Broad or Narrow? 

• Ghaemi SN, Lenox MS, Baldessarini RJ.  Effectiveness and safety of long-term antidepressant treatment in bipolar disorder.  J Clin Psychiatry 2001 Jul;62(7):565-569 (their review of 7 double-blind studies: conclusion -- increased caution warranted but too few data overall). 

• Antidepressant-associated mania or psychosis: 10% of all psychiatric admissions in one study

• Dr. Gary Sachs at Harvard: a case illustration

• Dr. Ron Pies' experience and advice  (a regular columnist for Psychiatric Times); October 2003 also^Pies

• For an extreme view, see the opinions of Dr. Glenmullen (Harvard adjunct clinical faculty)
      - His view: Use Prozac and other SRI's with great caution even in unipolar depression
      - See his book, Prozac Backlash 
          (full of inflammatory phrases, designed to frighten people)
          (but if the language was more careful, his points might be seen as worth considering)
          (and the chapter on suicidality induced by Prozac is calmer, well referenced)
      - See an opposing view from the National Mental Health Association (NMHA)
  

• Antidepressant "poop-out" associated with severe, treatment resistant illness: 
  "METHOD: I describe 15 cases who had a loss of response to repeated trials of antidepressants before developing a chronic and severe, refractory depression. RESULTS: ...Following discontinuation of antidepressants and treatment with mood stabilizers, there was a sustained improvement."  J Affect Disord 2001 Apr;64(1):99-106.
      

Less caution necessary

• September 2004 review and meta-analysis

• Recent Bipolar Network News summary (lead article)
  See their analysis of why we see differing observations of antidepressant risk

• Young et al
  Adding a antidepressant to a mood stabilizer (versus adding another mood stabilizer)

• Amsterdam et al have published at least three studies showing patients with bipolar disorder doing well on antidepressants and low rates of worsening:   

  Fluoxetine 2004
  venlafaxine (Effexor)
  Fluoxetine 1998

In one study (Fluoxetine 2004) the assessment of worsening was the Young Mania Rating Scale (YMRS).  If it did not increase more than 7 points, this was scored as "no switch" into hypo/mania.  If you look closely at this scale, you'll note that you could get no sleep at all (4 points) and feel extremely irritable (as long as you don't act it out with the rating person; thus 2 points), for a total of 6 points, and this would not classify as hypomania on the YMRS.  The test clearly looks more for bipolar I features (e.g. delusions, lack of insight, disorganized thought) than bipolar II features. 

• Moller et al
  The European view is also less cautious.

• Coryell et al openly question the idea that antidepressants cause rapid cycling. (However, looking closely at their results (namely, Table 2), they actually do find a very small association between rapid cycling and antidepressant use ("The proportion of weeks with SSRI treatment was low in both groups but significantly higher for those with rapid cycling").  )

For another summary of recent presentations and thinking -- though not a whole lot more data to go on -- see an excellent review on this issue by John McManamy on his well-organized and frequently updated site Depression and Bipolar Web.