Bipolar Diagnosis Rules Have Been Changed

Well, that might be a bit of an overstatement. But that's journalism, right?

Here's what really happened. The International Society for Bipolar Disorders (ISBD) is a group of researchers and clinicians interested in bipolar disorder, with members from all around the world. The leadership of this organization decided several years ago that we needed an update on the DSM (Diagnostic and Statistical Manual), because the next edition of that official rulebook won't come out for another three or four years.

The current DSM was written about 15 years ago. You would hope that by now we might have some additional insight into the nature of bipolar disorder and how it should be diagnosed.

So the ISBD commissioned 25 mood specialists to look at the existing literature on bipolar disorder and make recommendations in a different areas of controversy: mixed states, Bipolar II, bipolar depression (how is it different, if at all, from unipolar depression?), rapid cycling, children and adolescents, and the "bipolar spectrum" perspective.

For intrepid interested readers, I have posted a summary of these guidelines, with the relevant links, on my PsychEducation website. The bottom line, from my point of view: virtually all of the papers prepared by this committee of bipolar specialists acknowledge that the DSM system of discrete categories -- in which one either has unipolar depression, for example, or bipolar depression, but nothing in between -- is causing some trouble. While switching over to a "spectrum" perspective, as reflected on my website, is not a solution either (all sorts of logistic problems would follow), the validity of that way of thinking is supported by the work of these experts.

Dr. Phelps

So although the official rules for bipolar diagnosis have not literally changed, an important update on those rules has been issued. Anyone who depends on the rule system -- which hopefully includes a broad array of patients and practitioners -- should be interested in further details on the work of the ISBD Committee on Diagnosis. Here is the summary link again.

The Value of Low-Dose Lithium

A reader asked if I would comment on whether low doses of lithium, well below the high-risk levels that can swing up into "lithium toxicity", might still have benefit -- particularly in Bipolar II depression.

The answer is clearly yes. Indeed, lithium has shown value at low doses as an add-on treatment for "unipolar" depression. In other words, lithium has value even if there is no obvious bipolar component to one's depression. And, it has value at low doses: when added to other medications that are not working well enough, it can boost their effects.

(On the other hand, we could wonder whether there might perhaps have been an "bipolar component" in the person's depression, and that is why the antidepressant was not working well enough -- and why lithium helped. In other words, does lithium helping mean that there might have been some degree of bipolarity in the depression? For the moment, until we have a better way of knowing when bipolar disorder is present, in any degree, we should assume that the answer to this question is no. That is, we should assume lithium can treat depression of any kind, not just bipolar depression.)

Recent data suggest that lithium's benefit in bipolar disorder is stronger against preventing manic recurrences, than against preventing depression recurrences. Nevertheless, many of us use it for a very different purpose, namely adding some antidepressant "oomph" when other treatments have not effectively treated depression. In this role, sometimes tiny doses of lithium are sufficient. One of my patients even responded to 150 mg, half of the usual smallest dose. Her response was unequivocal, and has been sustained for over three years now.

What about blood levels? At these low doses, the level of lithium can be far below the "therapeutic range". On the laboratory data sheet, such a result is often marked with an L, indicating an abnormal value, in this case too low. This can worry people who don't really understand what we are doing here. When lithium is used at a low dose, as an add-on medication, we are usually targeting a particular symptom that is already present -- usually depression (as opposed to targeting the prevention of recurrence when a patient is well. That requires knowing that the lithium level is sufficient to award that benefit. We know from research and experience that this requires requires being in the "therapeutic range". Indeed, that range is defined by a lower limit below which the preventive benefit is unlikely to occur; and an upper limit beyond which dangerous side effects become common).

In the low- dose approach, one simply turns the dose up until the target symptom is responding, or until a side effect appears, or until the patient reaches 600-900 mg, at which point we get our first blood test to make sure that she/he is not approaching the upper end of the therapeutic range.

If a good response occurs at a very low dose, e.g. 300-600 mg, the blood level is likely to be low -- so it is important to be prepared for that low number, prepared to disregard it. The main reason for the test is simply to establish that the level is not near the upper end of the therapeutic range, which even at low doses can occur sometimes. It is safe to be at that upper level, but then one has to be more careful about anything that can raise lithium levels spontaneously (for example: dehydration, adding a blood pressure medication, using ibuprofen, getting the flu). One has to be careful about such factors in any case, but when the lithium level is known to be high, then any such changes may warrant repeating the lithium level to be sure it has not gone too high. Knowing that the level is "low" allows for a little more breathing room in this respect.

In summary: low-dose lithium is a great medication. It is inexpensive, and under these circumstances can often be taken with no side effects at all. The risk to one's thyroid production is still there, and long-term monitoring of kidney safety is still warranted (although that risk is likely to be much lower with the lower dose).

I tell my patients: lithium is like two different medications. Low- dose lithium is a "low-maintenance" medication, whereas high- dose lithium warrants careful attention to levels and other variables. Unfortunately, when most people think of lithium, they think of the high-dose approach and may therefore overlook a really excellent medication option.

Thanks to anonymous for the question.
Dr. Phelps

Dr. Drug Rep: Thoughts on Working Too Closely with Pharmaceutical Companies

For a first-hand account of how physicians are working with pharmaceutical companies as speakers -- which I have done extensively in the last several years -- read a very frank one published last week in New York Times Magazine, by Dr. Daniel Carlat: Dr. Drug Rep.

Having had the privilege of meeting Dr. Carlat, I know that he holds himself to a firm ethical standard. You can see that in his article. But I have continued to give talks for a few select pharmaceutical companies, whereas he found the process ethically unacceptable. Am I violating a standard? Am I only fooling myself, to think that I have not?

Linking his essay, I posted the following paragraphs on my website on the page in which I explain how I use pharmaceutical company funding. I'm trying to be quite public about taking money for giving talks about bipolar disorder, to force myself to be as honest as possible about this practice. (Or am I using these posts as another false shield? I don't think so, but I must admit there is no way for me to really know.)

From the website, revised today:
You would have to ask someone who has attended one of my talks to confirm this, but I still think -- after going through the exact same thought process that Dr. Carlat describes -- that I am managing to stay neutral. Oh, I still show the company slides where required, and emphasize (for example) "this is what AstraZeneca wants you to know". But as quickly as possible we move to a discussion of bipolar diagnosis; and when we come around to treatment, I moderate an open-ended discussion in which I try to emphasize treatment approaches with solid, well accepted evidence for their efficacy. I only give talks for companies whose medications meet that criterion, so I am not -- I don't think -- in Dr. Carlat's position.

Indeed, I once gave talks for Wyeth, the company he uses as an example. When they required that I use their slides, as he describes, I declined any further invitations to speak for them. But before that, I did give a talk once for Wyeth in which I found myself promoting Effexor, just as Dr. Carlat did (after the same training experience with Drs. Thase and Sussman, who had a similar influence on me). I had the same feeling he describes: "whoops, I just went over the line". I remember that particular talk vividly (Dr. Robert Burton, a local internist colleague, was there, for example). I still feel guilty about that one. I don't want to have that feeling again.

Dr. Phelps

Antidepressants and Suicide: Biologic Marker?

Once in a while a single research study really advances our field. I think it just happened again.

Psychiatry is making major advances in terms of understanding the genetic, molecular, and brain-structure basis of some of the illness is that we treat. Frankly, this is the best field and medicine to be in right now -- at least in terms of watching good science happen. (It might be one of the worst in terms of how badly our current health care system is treating people with mental illnesses).

In any case, here is an interesting new result. The study was made possible as part of a huge study of depression in the United States (funded by our taxpayer dollars, one of the best uses I can think of -- in some ways this was like the Hubble telescope of mood disorder research).

The bottom line: even though many psychiatrists have criticized the FDA for placing a warning label on antidepressants about their potential for inducing suicidal thinking; and even though some evidence has emerged suggesting that the warning may have increased suicide rates by decreasing antidepressant use (this is still quite controversial); it would be nice to know if antidepressants really cause suicidality at all, even if rarely. This new study provides further evidence that indeed such a phenomenon occurs, as a result of the antidepressants.

But the study goes one step further: it identifies two genes which seemed to be associated with this new onset of suicidal thinking when an antidepressant is used (interestingly, the genes are not associated with suicidal thinking itself, which none of the patients in the study had before they received the antidepressant).

For more, see my Antidepressants and Suicide webpage.
Dr. Phelps

See? Sleep deprivation is not good: look at this picture

Evidence implicating sleep deprivation as one of the central ingredients in bipolar mood problems just keeps racking up. Thanks to Nancy and John for sending me a link with a remarkable picture I hope many readers here will take a moment to view.

Sleep deprivation increases activity in the amygdala, a brain region associated with strong emotions such as fear and agitation. In some ways, this is no surprise: getting more emotional, less able to control one's expressions of anger or sadness, is a familiar consequence of getting too little sleep. But if you want to see a dramatic demonstration of the brain basis of this phenomenon, see a brief explanation of this new research on my webpage about sleep and the biological clock, part of the Biological Basis of Bipolar Disorder series. Or see Dr. Walker's press release.

Dr. Phelps

Why Does It Take so Long?

You may know the story about lithium. It was discovered from a mistaken focus on urate. Until today, however, I did not realize that the first use of lithium was not in 1948 by Dr. John Cage in Australia -- but rather, nearly a century before, in 1871. (Here is a very brief little history of lithium).

Why does it take so long for an effective treatment to be recognized?

Certainly it helps if there is a pharmaceutical company spending millions of dollars on advertising. A medication like olanzapine (Zyprexa), for example, sprung into widespread use within a few years after its release -- in part because one only needs to prescribe it a few times before recognizing that it has remarkable effectiveness. (Unfortunately, one only has to prescribe it a few times more than that before discovering that it has remarkable weight gain effects as well).

Recently I have become interested in two treatment approaches for bipolar disorder which, lacking pharmaceutical company advertising, could easily go several decades relatively unnoticed. Neither of them is clearly established as an effective treatment yet, in part because there is no pharmaceutical company funding research.

First, we have the new data arriving about use of thyroid hormone as a mood stabilizer. This is a very unusual approach relative to the standard recommendations. Learn more on my webpage posted today about high-dose thyroid hormone.

Second, regular readers here will probably have come across my enthusiasm for darkness as a potential mood stabilizer. This too has very limited data supporting its use, but it is cheap and widely available and unlikely to be harmful and therefore worth knowing about. See my webpages on Dark Therapy, and the related big-picture view of this approach, Light and Darkness In Bipolar Disorder.

Maybe in this age of aggressive patient self-education, and widespread Internet access, it will not take so long for a treatment -- even one without $millions in advertising -- to become widely known.

Dr. Phelps

Fibromyalgia And Bipolar Disorder

Courtesy of a brave man who has bipolar disorder, and whose son has both bipolar disorder and fibromyalgia, here's a remarkable statistic.
Patients with fibromyalgia are twice as likely to have Major Depression as are patients with rheumatoid arthritis. (The latter, RA, was selected in this study as a comparison group because it has a relatively well-established basis in an immune system malfunction; or as the basis for fibromyalgia is still very unclear but does not appear to be a straightforward autoimmune problem like RA).

But here is the remarkable part: by comparison, patients with fibromyalgia are 153 times more likely than those with RA to have bipolar disorder.

Makes you wonder what is going on, doesn't it? The fellow who forwarded this to me wonders if exposure to antidepressant medications, in people who have bipolar disorder, might be the basis for this connection. So far, to my knowledge, there is nothing more than that striking statistic above to even raise that possibility. It does make you think, though, doesn't it?

Dr. Phelps

Misdiagnosis and Antidepressants: Any Progress?

A reader who appears to have been following my website for years writes:

"It is still astounding to me that so many psychiatrists seem to not know that treating someone with (undiagnosed) bipolar disorder, in a severe depression, can cause a 'tipping' into mania."

So we might ask: how bad is this mis-or under-diagnosis problem? Is it still as bad as it was? And how many psychiatrists really are unaware that antidepressants can precipitate a manic episode?

As we proceed, we might also wonder if there is any evidence that the pendulum swing toward increased diagnosis of bipolar disorder has gone too far, causing unintended consequences on the opposite side -- people being treated with medications for bipolar disorder, with their known risks and side effects, who really do not need this treatment.

Taking each of these questions, and summarizing very briefly (one could write nearly an entire book summarizing the research and opinions on each of these questions):

1. How bad is the problem? A few years ago, it was this bad (the graph below reflects one study, but several showed a nearly identical result):

Well drat. Can't get that image to upload. Suffice to say that in a study published in 2000, presumably reflecting trends in late 1990's, at that time it took 6 years to get a correct diagnosis of Bipolar I, and 12 years for Bipolar II.

To my knowledge, there have been no similar studies published more recently that might show us changes in this problem.

2. Is there any evidence that the pendulum has swung too far in the opposite direction?

If judging simply on the basis of public outcry,certainly there is reason to worry.There is a lot of noise these days about overdiagnosis of bipolar disorder, particularly in children. There is one study (Soutullo et al) which seriously questions the rate of diagnosis of bipolar disorder in children in the United States.

In talking with doctors who are worried about overdiagnosis,it seems that the main concern isabout exposing people -- especially children --to the risks of medications we use for bipolar disorder. In particular, the risk of weight gain, which comes along with so many of the medications for bipolar disorder, is concerning -- given the prevalence of weight gain even without such medications in our society, and the evidence that severe mood disorders themselves seem to be associated with weight gain. This is a very valid concern.

Nevertheless, we should probably not be positioning our diagnostic pendulum based on medication risks, or at least that is not supposed to be another process works. Alternatively, if we are to let medication risks influence our diagnostic judgment, then the issue of how much risk antidepressants pose in the short and long run is a very important variable. Readers who have gotten this far might be interested in my essay for psychiatrists along these lines, which appeared in a journal called Psychiatric Times.

3. How many psychiatrists are unaware that antidepressants can trigger manic episodes?

Frankly, I think this number is probably quite low. The problem lies more with the primary care providers who are struggling to cope when they cannot refer patients to a psychiatrist (because in many regions of the country, particularly here in the West, it is difficult to find a psychiatrist who can see a patient within a few weeks, and for many it is months, and some not at all). These current care providers have not had good training in the diagnosis of bipolar disorder. And they have very little experience in using the mood stabilizers for this condition. That makes them reluctant to make the diagnosis, because they are reluctant about being led into having to treat it. The result is an over-reliance on antidepressant medications, which makes them perhaps reluctant to look at potential risks of these medications.

All of this was the basis, in part, for writing my website on bipolar II (PsychEducation.org). Since that time, six years ago, I think there has been substantial improvement. But it is slow, and there is a long way to go. On top of all this, we now have to counter that concerned that greater diagnosis of bipolar disorder will lead to many children being placed on medications that will lead to massive weight gain and other problems. If all we did was simply demand that anyone who is about to receive an antidepressant medication be screened with accepted instrument for bipolar disorder, such as the Mood Disorders Questionnaire, that would be a big step forward.

Dr. Phelps

Does Aripiprazole (Abilify) Have Antidepressant Effects?

The short answer is: probably yes. A much longer answer has just been posted as an update to my webpage about aripiprazole and the "atypical antipsychotic" family of which it is a member.

If for one reason or another you are interested in the data on aripiprazole in bipolar depression, or Major (unipolar) Depression, I've summarized four studies, the three of them unpublished so far, which have recently been made available by the manufacturer.

See New Data on Aripiprazole.

JP

Worsening Over Time: The Progression of Bipolar Disorder

In some people, bipolar disorder gets worse over time. Not everyone. And treatment is supposed to prevent this, at least in the best of cases.

The graph above shows one hypothetical patient's experience, where depression is shown as a bar below the line, a manic episode as a bar above the line, and hospitalizations in red. The height of the bar indicates the severity of the episode. Fortunately, few cases are as bad as this, but the pattern is obvious -- and that pattern is very common.

In Bipolar I, where episodes tend to be separated by "well intervals", one can see a progression like the one shown above: episodes become more severe, and the length of time in between episodes become shorter. In Bipolar II, more continuous symptoms are common. In this case, illness progression is characterized by an increasing severity of mood swings, and sometimes more rapid cycling. In many people, manic and depression symptoms occur at the same time, and what is called a "mixed state". In other words, the pattern shown in the graph above is not easily seen in people who have more complex and mixed symptoms. Yet the progression toward more severe symptoms over time is still going on.

Unfortunately, this also means that sometimes a treatment which worked at one point is no longer sufficient to provide complete symptom control later. Sometimes a person who symptoms were quite well-controlled on one medication ends up on three a few years later.

What causes this progression? This is not well understood, in part because we do not know what causes the illness itself; we do not know what the molecular and genetic basis of bipolar disorder is (although we know a lot more than we did 10 years ago, as outlined on my webpage about "what causes bipolar disorder?"). However, we do know some of the factors which seem to influence whether people experience this can progression or not, and how fast.

Basically, mood specialists currently presume that anything which has a "destabilizing influence" is likely to be one of the causes of progression. You can imagine how hard it is to do research on this: people continue to live their lives, and thus expose themselves to all sorts of influences. How could you tell whether the influence you are studying was truly the "cause" of worsening? There are always too many variables to really know.

For now, we are extrapolating from our experience with the obvious triggers. Probably the biggest one is substance use. Methamphetamine and cocaine might be the worst. Alcohol comes along shortly after that: even though in the short run it can damp down symptoms, in the long run it tends to cause more cycling in most people. Pain medications are not as bad, and it seems, at least in our current understanding. They can cause trouble in some people but nowhere near as often as street stimulants and alcohol.

What about marijuana? Evidence has accumulated that this can lead to psychotic episodes in susceptible individuals. In Bipolar I, therefore, it might be best avoided entirely. At the same time, many patients who see me in our local free clinic have been using marijuana for years, just a puff or two at night, because they have found that it helps them sleep. They are quite certain they would be worse without it, although they tend to give it up if they get a very good response to a mood stabilizer medication (in which case I can claim"my drugs are better than your drugs").

The other big destabilizing influence is sleep deprivation. People who take on erratic schedules, such as shift work, often see a dramatic worsening in mood stability. Even just a plane flight across time zones can be a major trigger in some susceptible individuals. Evidence is accumulating that careful attention to sleep schedule, and even light exposure, is very important in self-management of bipolar disorder. See my essay on Light and Darkness in Bipolar Disorder for some interesting data about the role of darkness independent of sleep.

Finally,without necessarily having exhausted this list, a word about antidepressants. One of my greatest fears about current psychiatric practice is that 10 years or more from now we might discover that widespread use of antidepressants has led to an acceleration in bipolar progression in people receiving these medications, in those who were later discovered to have bipolar disorder (let alone those who were known at the time to have bipolar disorder). This acceleration has been called "kindling", after a similar phenomenon seen in epilepsy. I sure hope that I'm wrong about this. Until we have a good biological marker of Bipolar Disorder which can show us where a person is on this illness progression, so that we might be able to see -- literally -- progression associated with antidepressants, this kindling worry is likely to remain just that, a background worry, not a known problem. See more about this on my page about Antidepressant Controversies, the section on kindling.

(This entry was composed in response to a reader's request for information on this topic. Thank you for the inquiry)

Dr. Phelps