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Abilify for Bipolar Maintenance: More Hard Questions

Much attention has been drawn to a recent PLoS Medicine article criticizing the evidence base for the use of Abilify as maintenance treatment for bipolar disorder.  The major points emphasized by most critics are, first, that the FDA approved Abilify for this purpose in 2005 on the basis of flawed and scanty evidence and, secondly, that the literature since that time has failed to point out the deficiencies in the original study.

While the above may be true, I believe these criticisms miss a more important point.  Instead of lambasting the FDA or lamenting the poor quality of clinical research, we psychiatrists need to use this as an opportunity to take a closer look at what we treat, why we treat, and how we treat.

Before elaborating, let me summarize the main points of the PLoS article.  The authors point out that FDA approval of Abilify was based on only one “maintenance” trial by Keck et al published in 2007.  The trial included only 161 patients (only 7 of whom, or 1.3% of the total 567 who started the study, were followed throughout 26 weeks of stabilization and 74 follow-up weeks of maintenance).  It also consisted of patients who had already been stabilized on Abilify; thus, it was “enriched” for patients who had already shown a good response to this drug.  Furthermore, the “placebo failures” consisted of patients who were abruptly withdrawn from Abilify and placed on placebo; their relapses might thus be attributed to the researchers’ “randomized discontinuation” design rather than the failure of placebo.  (For more commentary, including follow-up from Bristol-Myers Squibb, Abilify’s manufacturer, please see this excellent post on Pharmalot.)

These are all valid arguments.  But as I read the PLoS paper and the ongoing discussion ever since, I can’t help but think, so what??  First of all, most psychiatrists probably don’t know about the PLoS paper.  And even if they did, the major questions for me would be:  would the criticism of the Keck et al. study change the way psychiatrists practice?  Should it?

Let’s think about psychiatric illness for a moment.  Most disorders are characterized by an initial, abrupt onset or “episode.”  These acute episodes are usually treated with medications (plus or minus psychotherapy or other psychosocial interventions), often resulting in rapid symptomatic improvement—or, at the very least, stabilization of those symptoms.

One big, unanswered (and, unfortunately, under-asked) question in psychiatry is, then what?  Once a person is stabilized (which in some cases means nothing more than “he’s no longer a danger to himself or others”), what do we do?  We don’t know how long to treat patients, and there are no guidelines for when to discontinue medications.  Instead we hear the common refrain:  depression, schizophrenia, and bipolar disorder, are lifelong illnesses—”just like hypertension or diabetes”—and should be treated as such.

But is that true?  At the risk of sounding like a heretic (and, indeed, I’d be laughed out of residency if I had ever asked this question), are there some cases of bipolar disorder—or schizophrenia, or depression, for that matter—which only require brief periods of psychopharmacological treatment, or none at all?

The conventional wisdom is that, once a person is stabilized, we should just continue treatment.  And why not?  What doctor is going to take his patient off Abilify—or any other mood stabilizer or antipsychotic which has been effective in the acute phase—and risk a repeat mood episode?  None.  And if he does, would he attribute the relapse to the disease, or to withdrawal of the drug?  Probably to the disease.

For another example of what I’m talking about, consider Depakote.  Depakote has been used for decades and is regarded as a “prototypical” mood stabilizer.  Indeed, some of my patients have taken Depakote for years and have remained stable, highly functional, and without evidence of mood episodes.  But Depakote was never approved for the maintenance treatment of bipolar disorder (for a brilliant review of this, which raises some of the same issues as the current Abilify brouhaha, read this article by The Last Psychiatrist).  In fact, the one placebo-controlled study of Depakote for maintenance treatment of bipolar disorder showed that it’s no better than placebo.  So why do doctors use it? Because it works (in the acute phase.)  Why do patients take it?  Again, because it works—oh, and their doctors tell them to continue taking it.  As the old saying goes, “if it ain’t broke, don’t fix it.”

However, what if it is broke[n]?  Some patients indeed fail Depakote monotherapy and require additional “adjunctive” medication (which, BTW, has provided another lucrative market for the atypical antipsychotics).  In such cases, most psychiatrists conclude that the patient’s disease is worsening and they add the second agent.  Might it be, however, that after the patient’s initial “response” to Depakote, the medication wasn’t doing anything at all?

To be sure, the Abilify study may have been more convincing if it was larger, followed patients for a longer time, and had a dedicated placebo arm consisting of patients who had not been on Abilify in the initial stage.  But I maintain that, regardless of the outcome of such an “improved” trial, most doctors would still use Abilify for maintenance treatment anyway, and convince themselves that it works—even if the medication is doing absolutely nothing to the underlying biology of the disease.

The bottom line is that it’s easy to criticize the FDA for approving a drug on the basis of a single, flawed study.  It’s also easy to criticize a pharmaceutical company for cutting corners and providing “flawed” data for FDA review.  But when it comes down to it, the real criticism should be directed at a field of medicine which endorses the “biological” treatment of a disorder (or group of disorders) whose biochemical basis and natural history are not fully understood, which creates post hoc explanations of its successes and failures based on that lack of understanding, and which is unwilling to look itself in the mirror and ask if it can do better.

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28 Responses to Abilify for Bipolar Maintenance: More Hard Questions

  1. moviedoc says:

    What’s your point? As soon as the patient gets better stop the medication to see if they get worse again? Do you suggest that because the “biochemical basis and natural history are not fully understood” we should, what, not treat them? send them for psychoanalysis? snake oil? fish oil? You want to criticize a “field” of medicine. Where does that get us? We have more than enough blame and criticism. What we need is better science and understanding. That costs money. Criticism is cheap. If you want to help the doctors help real patients tell us what to do differently.

    • stevebMD says:

      “As soon as the patient gets better stop the medication to see if they get worse again?”

      Of course not. As I wrote, I have patients who have been on Depakote (or Abilify, or Geodon, or Zyprexa…) for years and are doing just fine.

      Do you suggest that … we should not treat them?

      Again, no.

      My points are: (1) We do things (“in the name of treatment”) even when the evidence for them is flimsy or nonexistent, and that should give us pause; and (2) the foundation upon which we develop our treatments is questionable. Give me one good mechanistic argument why a dopamine system stabilizer like Abilify should prevent a manic episode in someone with bipolar disorder. (Come to think of it, explain to me what bipolar disorder is in the first place.) I’m not saying Abilify doesn’t work– it does. In some cases. In those cases where it does not– and we want to develop improved therapies– I agree we need a better understanding of the biology, the phenomenology, and the natural history of the disease (whatever it is), rather than just throwing more drugs into the mix.

      • moviedoc says:

        Agree with all you say, but we still need constructive ideas. The bipolar concept is what it is. Best we can do now. If you don’t want to throw more drugs at a patient there’s ECT, rTMS, and VNS, not to mention light. We may never have the answers to your questions. But in the meantime we’re stuck with trial and error, unless you can suggest a better approach.

    • Iatrogenia says:

      Let me see — you’d rather medicate unnecessarily than to concede that perhaps your role in the patient’ life is over?

      Let me suggest something: Taper your remitted patients very, very gradually off the medications they no longer need. Safe tapering may take a year. Then refrain from diagnosing withdrawal symptoms from relapse.

      You may be surprised at how many of your patients don’t need you anymore.

  2. Gary says:

    I’ve never read a Formulation or Plan that states, to the effect: Although there are some symptoms present, they do not justify the use of something as toxic as Depakote (or antipsychotic). The mere presence of symptoms does not automatically indicate that a medication with potential for severe complications be prescribed. My training involves learning when NOT to prescribe, and this is one of those times.

    The bias to intervene is irrational. Not intervening is also treatment, and, in fact, is the mark of expertise.

    • moviedoc says:

      “The bias to intervene is irrational. Not intervening is also treatment, and, in fact, is the mark of expertise.”

      Very true, but ignorant judges and juries without benefit of adequate expert testimony drive that bias. Holding physicians responsible for the behavior of others puts money in the pockets of plaintiffs and their lawyers.

  3. BelcadiMD says:

    It’s really difficult to agree with the indication that Abilify has gotten on that study only; One it’s a small sample,second it’s a short period of time;
    What if those patients would ‘naturally’ only be symptomatic every 4 years? I do tend to agree with Steve though….if they’re doing well on it why stop it?
    Especially ( even though we don’t know much about it ) when you have what appears to be a highly recurrent mood disorder..

    • Iatrogenia says:

      What other medical specialty insists on medicating patients who show no need of the medication? What other medical specialty refuses to evaluate risk-benefit at every stage of treatment?

      Is the mood disorder recurrent, or have you been misdiagnosing drug withdrawal syndromes as relapse? Why are all your patients chronic?

      • moviedoc says:

        I suppose Iatrogenia you would have women stop — oh, excuse me, taper — their oral contraceptive because they haven’t gotten pregnant yet. And you would have diabetics stop their insulin as soon as their blood sugar is within normal limits. And you would have patients with hypertension stop their antihypertension meds as soon as their blood pressure is in the normal range, and when it goes up again you call it “withdrawal.”

        The question is: What medical specialty doesn’t medicate patients who show no need of the medication?

      • Jackie says:

        Iatrogenia, — clever name by the way — the points you bring up could be addressed just as easily to neurologists and endocrinologists. And as a friend recently learned, to urologists. In fact, you could address them to all medical specialties.

        And on withdrawal from medication, there are plenty of scientific papers about withdrawal effects and psychiatric drugs. Just go to “Google Scholar” or “pubmed.” You’ll also find info on the PIs for the drugs, too.

      • Iatrogenia says:

        Jackie — I am very familiar with ALL the literature on withdrawal. It far understates the severity of withdrawal symptoms and the extent of withdrawal syndrome, which can last weeks, months, or years. Why it understates that information is the subject of every article on drug company influence in psychiatry.

        (If you would like to see what withdrawal syndrome is really like, visit SurvivingAntidepressants.org, a patient peer support site.)

        However, despite the extensive (albeit minimizing) documentation of withdrawal syndrome, psychiatrists almost invariably misdiagnose withdrawal symptoms as relapse, and unnecessarily medicate for years. This is simply to avoid withdrawal, although they tell their patients they need to avoid relapse.

        There are no published psychiatric protocols for tapering patients off drugs. Doctors don’t know what “tapering” means — many are still telling patients to alternate dosages. Alternate dosages of short half-life medications! What do you think happens then? The vague information about tapering in the PIs is a CYA gesture.

        If you think that is sufficient information about safe tapering, I suggest you educate yourself.

  4. Jackie says:

    Once stabilized, patients/doctors may be reluctant to change doses of or stop certain Bipolar medications because of the time involved in ratcheting up to a therapeutic dose, and toxicity issues.

    For example, it can take months for a patient to get up to the “right” dose of “mood stabilizers” lamotrigine or lithium. If a medication such as this is later tapered off, and the patient subsequently has a manic or depressive episode, then it will take months to get up to the “right” dose again. And, with lithium there will be all the labs to redo.

    For someone with a history of cycling a couple of times a year, it might indeed make more sense to stay on the meds. This really is an area that needs study.

  5. moviedoc says:

    Everybody says we need more studies, and as Steve reminds us, not just to find out which drug works best but even to better define diagnostic categories. Why not tax the bejesus out of pharma instead of having them pay millions for their own studies. FDA, or somebody, could dole out the money to academic researchers with no pharma strings. FDA could use the data to decide which drugs (or devices) should be approved for treatment of which conditions.

  6. Jackie says:

    “Come to think of it, explain to me what bipolar disorder is in the first place.”

    — Wish I could explain that! As I’ve mentioned before, I’m going through the BP Disorders journal and the researchers publishing there talk of the heterogeneous nature of BP and how that makes it difficult to come up with definitive answers. A few examples : The early-onset group seems to be different from the late-onset group, the BP II group seems to be more similar to the MDD group than to the BP I group, lithium responders seem to be different from non-lithium responders, and so on.

    Maybe. As they say, “more studies are needed.”

  7. I think we do have to ask ourselves what “bipolar disorder” is…

    And we have to be honest.
    And admit that we simply do not know.

    Even the textbook cases… the ones where the first “episodes” start in the late-teens and early-twenties.

    We don’t really know.
    Do we?

    I’ve read studies that show that 80 percent or more of people who have symptoms that we call “bipolar disorder” have experienced trauma…
    The question I suppose is what type of trauma, blatant or subtle… from the family of origin or someone/someplace else.

    In those cases, how do we help the person overcome the trauma?
    Keyword, “overcome.”

    I think some people benefit from “talk therapy”, but not everyone.
    Others do well with meditation/mindfulness, meridian-based therapies for left brain/right brain integration, etc… There are lots of options.

    Even if a high percentage of people have experienced trauma, even if it’s as high as 80 percent, there are still 20 percent whose symptoms come from other areas – IMO, we need to look at the thyroid, the adrenals, hypoglycemia, food allergies, nutritional deficiencies, etc.

    I believe in the “kindling” theory.
    Thoughts are related to mood.
    Moods and behaviors become habit.

    People can change their thoughts.
    They can also make other lifestyle changes.
    We are what we think.
    We are also what we eat.
    Who we surround ourselves with.
    What we do.

    How do we help people move into new habits?
    Habits that are more healthy?
    Habits that promote well-being, and better functioning?

    Psychiatric drugs may have a role in the short-term, for “psychotic episodes”… But not for the long term.
    Psychotic episodes are events.
    They do not define a person.

    How do we move beyond symptom management, and toward recovery, wellness, better functioning?

    I’m not sure there’s always an easy answer.
    Because I believe there are MANY answers that offer hope.
    Too many to list on one comment.

    Duane Sherry, M.S.
    http://discoverandrecover.wordpress.com/wellness

    • duanesherry says:

      Steve,

      I would like to apologize to you and your readers for having left so many back-to-back comments on previous posts.

      I would like to make one more quick-note on this post in reference to psychiatric drug withdrawal.

      You mentioned that psychiatry has not developed a protocol for drug withdrawal.

      A good book on the subject is ‘Your Drug May be Your Problem: How and Why to Stop Taking Psychiatric Medication’ – Peter Breggin, M.D. and David Cohen, Ph.D. –

      http://www.amazon.com/Your-Drug-May-Problem-Psychiatric/dp/0738203483

      In the book, Breggin talks about a 10 percent rule…
      Reducing a drug by no more than 10 percent at a time (slower when necessary)… once a person is stable, another 10 percent reduction.

      There are some good links on this page for any patient/doctor who is interested… scroll down 2/3 of the page) to find some good links –

      http://discoverandrecover.wordpress.com/warning

      Thank you for bringing up this subject.

      Duane Sherry, M.S.

      • stevebMD says:

        Duane,

        Thanks for the comment. Regarding drug withdrawal, I should say that, yes, there are resources (like Breggin’s book) that guide us in how to taper medications, but very little in the literature about when or why to do so. As a result, you have well-meaning doctors who see a positive response to a medication but who are unwilling to “take the chance” of discontinuing it– only to make matters worse when yet another symptom arises, to which we respond with another medication, and so on.

        It seems to be a science that we make up as we go along. Unfortunately, we often forget where we came from.

      • Iatrogenia says:

        Organized psychiatry has not published anything meaningful on psychiatric drug withdrawal protocols. It’s as though medication is presumed to be eternal.

        Very few psychiatrists know what “tapering” means. Some people can tolerate a reduction by only a fraction of a milligram a month. It can take them years to get off the unnecessarily high dosages prescribed of psychiatric medications, sometimes in combination. And even then they’ll still have withdrawal syndrome for months or years.

        The doctors who have published about psychiatric drug withdrawal have been marginalized by the profession.

        Withdrawal and withdrawal syndrome is the elephant in the room.

  8. Bravo, once again. I can scarcely believe you’re a real psychiatrist! Keep up the good work!

    • JanePhD says:

      Bravo, Iatrogenia. I would add that I don’t think that many psychiatrists (or at least those who conduct clinical trials) know the difference between a discontinuation syndrome and an actual relapse. Hint: a discontinuation syndrome can be avoided by a very slow slow tapering of medication.

      • Iatrogenia says:

        Thank you, Jane. I know, I run a Web site for tapering and prolonged antidepressant withdrawal syndrome: SurvivingAntidepressants.org. Read those stories and see the true state of clinical psychiatry.

        I would add further, to your point, that no study of antidepressant efficacy, including the execrable STAR*D study that switched thousands of patients from one drug to another, reports a single case of withdrawal syndrome, although they report incidence of relapse.

        It is highly likely that withdrawal syndrome has contaminated ALL studies of antidepressant efficacy as it was most likely included in the relapse statistics.

        A drug drawback became a drug advantage.

        This contamination further erodes the very slim statistical margin in favor of antidepressant efficacy. Personally, I would say it puts efficacy in the negative: antidepressants doing more harm than good.

  9. AntiPReality says:

    Isn’t there a big difference between acute and chronic pain?

    If the only real affect of a major tranquilizer (anti-psychotics are major tranquilizers), then that is what its use should be limited to.

    Unless we wish to tranquilize all day and all night.

    Just the side effects of anti-psychotics alone should give pause to issuing a prescription for anything other than acute use, unless it is actually demonstrated to help individuals over a long period of time.

    Which is the point. It hasn’t.

  10. Lacey says:

    It’s *absurdly unethical* to stop treating someone for a disorder that IS TRULY (almost always) ‘like diabetes or heart disease’ – I honestly believe that is the wisest possible way to explain mental illnesses.
    I myself went off treatment three separate times, weaned down incredibly slowly (despite being told to go on a new antidepressant and quit the old one cold turkey = dumb dumb dumb – doctors are just people too, remember), and after several months each and every time, had the worst mood swings imaginable. My life in every way basically died for about half a year while I was recovering from the last episode.
    My three friends + one acquaintance with unipolar depression, and one friend + one acquaintance with bipolar all had the same experience with stopping treatment – or never starting it in the first place, in two of those cases (one being depressed, the other bipolar). The episodes just keep on coming. I do have one friend who didn’t take meds, and had only one episode (so far – it’s been a couple years) of depression, so I see your point – but she’s a little loopy now, she gets all mushy one moment and super grouchy the next….

  11. Lacey says:

    Also, thanks for the info on Depakote (Is that valproic acid? Valproic acid fascinates me because it’s been used in the form of Valerian in Chinese medicine for a long time 🙂 ), it’s interesting I never knew it used to be ~ how Abilify is now, science- & politics-wise…

    Also, why not ECT as an ethical alternative to drug therapy? Think about it, it shocks the neural pathways that’ve been forged by depression/mania into a fresh start. Well,that’s how I think of it 😛 And it’s got amazing evidence backing how safe and effective it is nowadays.

  12. Altostrata says:

    It’s extremely common for patients and doctors to mistake withdrawal syndromes for a psychiatric disorder that demands drug treatment. It sounds like that’s what happened with you and your friends, Lacey.

    Appropriately gradual tapering can take many months or even years, depending on the individual’s tolerance for dosage reduction.

    The public has been grossly misled about the dependency issues with psychiatric drugs and the difficulty of going off them.

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